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The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of a variety of non-cancerous cells including blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix.^[1]^[2]^[3]^[4] Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.^[1]^[5]^[6]^[7]

History

The importance of a stromal microenvironment, especially "wound" or regenerating tissue, has been recognized since the late 1800s. The interplay between the tumor and its microenvironment was part of Stephen Paget's 1889 "seed and soil" theory, in which he postulated that metastases of a particular type of cancer ("the seed") often metastasizes to certain sites ("the soil") based on the similarity of the original and secondary tumor sites.^[8]

Its^{[clarification needed]} role in blunting an immune attack awaited the discovery of adaptive cellular immunity. In 1960, Klein and colleagues found that in mice, primary methylcholanthrene-induced sarcomas exhibited an antitumor immune response mediated by lymph node cells to cancer cells derived from the primary tumor. This immune response did not however affect the primary tumor. The primary tumor instead established a microenvironment that is functionally analogous to that of certain normal tissues, such as the eye.^[3]

Later, mice experiments by Halachmi and Witz showed that for the same cancer cell line, greater tumorigenicity was evident in vivo than the same strain inoculated in vitro.^[9]^[10]

Vasculature

A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor.^[11] Tumors smaller than 1-2 mm in diameter are delivered oxygen and nutrients through passive diffusion. In larger tumors the center becomes too far away from the existing blood supply, leading the tumor microenvironment to become hypoxic and acidic.^[12] Angiogenesis is upregulated to feed the cancer cells and is linked to tumor malignancy.^[13]

Endothelial cells and angiogenesis

In hypoxic environments the tissue sends out signals called hypoxia inducible factors (HIFs) that can stimulate nearby endothelial cells to secrete factors such as vascular endothelial growth factor (VEGF). VEGF activates the endothelial cells, which begins the process of angiogenesis, where new blood vessels emerge from pre-existing vasculature.^[14] The blood vessel formed in the tumor environment often doesn’t mature properly, and as a result the vasculature formed in the tumor microenvironment differs from that of normal tissue. The blood vessels formed are often “leaky” and tortuous, with a compromised blood flow.^[15]^[12] As tumors cannot grow large without proper vasculature, sustained angiogenesis is therefore considered one of the hallmarks of cancer.^[16]

In later stages of tumor progression endothelial cells can differentiate into carcinoma associated fibroblasts, which furthers metastasis.^[12]

Enhanced permeability and retention effect

The enhanced permeability and retention effect is the observation that the vasculature of tumors tend to accumulate macromolecules in the blood stream to a greater extent than in normal tissue. This is due to the “leaky” nature of the vasculature around tumors, and a lacking lymphatic system.^[17] The permeable vasculature allows for easier delivery of therapeutic drugs to the tumor, and the lacking lymphatic vessels contribute to an increased retention. The permeable vasculature is thought to have several causes, including insufficient pericytes and a malformed basement membrane.^[18]

Hypoxia

While angiogenesis can reduce the hypoxia in the tumor microenvironment, the partial pressure of oxygen is below 5 mmHg in over 50% of locally advanced solid tumors, compared to venous blood which has a partial pressure of oxygen at 40-60 mmHg.^[14]^[19] A hypoxic environment leads to genetic instability by downregulating genes involved in DNA repair mechanisms such as nucleotide excision repair and mismatch repair pathways.^[20] This genetic instability leads to a high number of mutated cells, and is associated with cancer progression.^[19] Periods of mild and acute hypoxia and reoxygenation can lead cancer cells to adapt and grow into more aggressive phenotypes.^[14]

Hypoxia causes the upregulation of hypoxia induced factors (HIFs), which are transcription factors that decides how cells respond to a lack of oxygen.^[12] HIFs induces the transcription of thousands of genes, some of which induces angiogenesis or furthers metastasis, leading, for instance, to increased cell migration and matrix remodeling.^[21]^[4] An increased HIF expression can lead tumor cells to shift their metabolism from aerobic to anaerobic, where they obtain energy through glycolysis.^[22] Cells with an elevated glucose metabolism produce lactate, which decreases the pH in the microenvironment from a neutral and healthy 7.35-7.45 to an acidic 6.3-7.0. This phenomenon is described as the “Warburg effect”.^[22]^[23] HIFs also regulate immune cells, and an increased expression can lead to the inactivation of anti-tumor functions. This furthers the survival of tumor cells and hinders anti-tumor treatment.^[22]

Stromal cells

In cancer biology, the stroma is defined as the nonmalignant cells which are present in the tumor microenvironment. The stroma comprises a variable portion of the entire tumor; up to 90% of a tumor may be stroma, with the remaining 10% as cancer cells. Many types of cells are present in the stroma, but four abundant types are fibroblasts, T cells, macrophages, and endothelial cells.^[24] The stroma surrounding a tumor often reacts to intrusion via inflammation, similar to how it might respond to a wound.^[25] Inflammation can encourage angiogenesis, speed the cell cycle and prevent cell death, all of which augments tumor growth.^[26]

Carcinoma associated fibroblasts

Carcinoma associated fibroblasts are a heterogeneous group of fibroblasts whose function is pirated by cancer cells and redirected toward carcinogenesis.^[27] These cells are usually derived from the normal fibroblasts in the surrounding stroma but can also come from pericytes, smooth muscle cells, fibrocytes, mesenchymal stem cells (often derived from bone marrow), or via epithelial-mesenchymal transition or endothelial-mesenchymal transition.^[28]^[29]

Extracellular matrix remodeling

Fibroblasts are in charge of laying down most of the collagens, elastin, glycosaminoglycans, proteoglycans (e.g. perlecan), and glycoproteins. As many fibroblasts are transformed into carcinoma associated fibroblasts during carcinogenesis, this reduces the amount of extracellular matrix produced, like collagen being loosely woven and non-planar, possibly even curved.^[30] In addition, carcinoma associated fibroblasts produce matrix metalloproteinases that cleave proteins.^[19] Carcinoma associated fibroblasts are also able to generate a track that a carcinoma cell can follow.^[31] In either case, destruction of the extracellular matrix allows cancer cells to escape from their in situ location and intravasate into the blood stream where they can metastasize systematically. It can also provide passage for endothelial cells to complete angiogenesis to the tumor site.

Destruction of the extracellular matrix also modulates the signaling cascades controlled by the interaction of cell-surface receptors and the matrix, and it also reveals binding sites previously hidden, like the integrin alpha-v beta-3 on the surface of melanoma cells can be ligated to rescue the cells from apoptosis after degradation of collagen.^[32]^[33] In addition, the degradation products may have downstream effects as well that can increase cancer cell tumorigenicity and can serve as potential biomarkers.^[32] matrix destruction also releases the cytokines and growth factors stored therein (for example, VEGF, basic fibroblast growth factor, insulin-like growth factors, TGF-β, heparin-binding EGF-like growth factor, and tumor necrosis factor, which can increase the growth of the tumor.^[30]^[34] Cleavage of matrix components can also release cytokines that inhibit tumorigenesis, such as degradation of certain types of collagen can form endostatin, restin, canstatin and tumstatin, which have antiangiogenic functions.^[30]

Matrix stiffening is associated with tumor progression.^[4]^[35] This stiffening may be partially attributed to carcinoma associated fibroblasts secreting lysyl oxidase, an enzyme that cross-links collagen.^[36]

Immune cells

Myeloid-derived suppressor cells and tumor-associated macrophages

Myeloid-derived suppressor cells are a heterogeneous population of cells of myelogenous origin with the potential to repress T cell responses. They regulate wound repair and inflammation and are rapidly expanded in cancer, correlating with that signs of inflammation are seen in most if not all tumor sites.^[37] Tumors can produce exosomes that stimulate inflammation via myeloid-derived suppressor cells.^[38]^[39] Tumor-associated macrophages are a central component in the strong link between chronic inflammation and cancer, and are recruited to the tumor as a response to cancer-associated inflammation.^[40] Unlike normal macrophages, tumor-associated macrophages lack cytotoxic activity.^[41] Tumor-associated macrophages gather in necrotic regions of tumors where they are associated with hiding cancer cells from normal immune cells by secreting interleukin 10, aiding angiogenesis by secreting vascular endothelial growth factor (VEGF) and nitric oxide synthase,^[19] supporting tumor growth by secreting epidermal growth factor^[42] and remodeling the extracellular matrix.^[19] Tumor-associated macrophages show sluggish NF-κB activation, which allows for the smoldering inflammation seen in cancer.^[43] An increased amount of tumor-associated macrophages is associated with worse prognosis.^[44]^[45]

Tumor-associated macrophages are associated with using exosomes to deliver invasion-potentiating microRNA into cancerous cells, specifically breast cancer cells.^[38]^[46]

Neutrophils

Neutrophils are polymorphonuclear immune cells that are critical components of the innate immune system. Neutrophils can accumulate in tumors and in some cancers, such as lung adenocarcinoma, their abundance at the tumor site is associated with worsened disease prognosis.^[47]^[48]^[49] When compared among 22 different tumor infiltrating leukocyte subsets, neutrophils are especially important predictors of survival for patients with solid tumors.^[48] Neutrophil numbers (and myeloid cell precursors) in the blood can be increased in some patients with solid tumors.^[50]^[51]^[52] Experiments in mice have mainly shown that tumor-associated neutrophils exhibit tumor-promoting functions,^[53]^[54]^[55]^[56] but a smaller number of studies show that neutrophils can also inhibit tumor growth.^[57]^[58] Neutrophil phenotypes are diverse and distinct neutrophil phenotypes in tumors have been identified.^[59]^[54]

Tumor infiltrating lymphocytes

Tumor infiltrating lymphocytes are lymphocytes that penetrate a tumor, having a common origin with myelogenous cells at the hematopoietic stem cell, but diverge in development. Concentration is generally positively correlated.^[42] However, only in melanoma has autologous tumor-infiltrating lymphocytes transplant succeeded as a treatment.^[60] Cancer cells induce apoptosis of activated T cells (a class of lymphocyte) by secreting exosomes containing death ligands such as FasL and TRAIL, and via the same method, turn off the normal cytotoxic response of natural killer cells.^[39]^[61]

T cells

T cells reach tumor sites via the circulatory system. The TME appears to preferentially recruit other immune cells over T cells from that system. One such mechanism is the release of cell-type specific chemokines. Another is the TME's capacity to posttranslationally alter chemokines. For example, the production of reactive nitrogen species by MDSCs within the TME induces nitration of CCL2, which traps T cells in the stroma of colon and prostate cancers.^[3]

Another T cell inhibitor appears to be the apoptosis inducer Fas ligand (FasL) that is found in the tumor vasculature of tumor types including ovarian, colon, prostate, breast, bladder and renal cancer. High levels of endothelial FasL are accompanied by few CD8⁺ T cells, but abundant regulatory T cells (T_regs). In preclinical models inhibiting FasL increased the ratio of tumor-rejecting T cells to T_reg cells and T cell–dependent tumor suppression. FasL inhibition also improves ACT efficacy.^[3] For many cancers, an increased frequency of in the tumor microenvironment is associated with worse outcomes for the individual. This is not the case with colorectal cancer; an increased frequency of T_reg cells may suppress inflammation mediated by the gut flora, which promotes tumor growth.^[62]

Reproduction

T cells must reproduce after arriving at the tumor site to further increase their numbers, survive hostile elements and migrate through the stroma to the cancer cells. The tumor microenvironment obstructs all three activities. The draining lymph nodes are the likely location for T cell clonal reproduction, although this also occurs within the tumor. Preclinical models suggest that the tumor microenvironment is the major site of cancer-specific T cell cloning and that the CD8⁺ T cell replicative response there is orchestrated by the CD103⁺, Baft3-dependent DC, which can efficiently cross-present cancer cell antigens, suggesting that therapeutic interventions that enhance CD103⁺ contribute to tumor control.

Research

Models

Several in vitro and in vivo models have been developed that seek to replicate the TME in a controlled environment. Tumor immortalised cell lines and primary cell cultures have been long used in order to study various tumors. They are quick to set up and inexpensive, but simplistic and prone to genetic drift.^[63] 3D tumor models have been developed as a more spatially representative model of the TME. Spheroid cultures, scaffolds and organoids are generally derived from stem cells or ex vivo and are much better at recreating the tumour architecture than 2D cell cultures.^[64]

Drug development

Advances in remodeling nanotherapeutics suppress cancer metastasis and recurrence.^[65] Researchers have discovered that the use of ferumoxytol suppress tumor growth by inducing transition of macrophages to proinflammatory types.^[66] Nanocarrier vehicles (~20–200 nm in diameter) can transport drugs and other therapeutic molecules. These therapies can be targeted to selectively extravasate through tumor vasculature.^[18]^[67] These efforts include protein capsids^[68] and liposomes.^[69] However, as some important, normal tissues, such as the liver and kidneys, also have fenestrated endothelium, the nanocarrier size (10–100 nm, with greater retention in tumors seen in using larger nanocarriers) and charge (anionic or neutral) must be considered.^[18] Lymphatic vessels do not usually develop with the tumor, leading to increased interstitial fluid pressure, which may block tumor access.^[18]^[70]

Therapies

Antibodies

Bevacizumab is clinically approved in the US to treat a variety of cancers by targeting VEGF-A, which is produced by both carcinoma associated fibroblasts and tumor macrophages, thus slowing angiogenesis.

Targeting immunoregulatory membrane receptors succeeded in some patients with melanoma, non-small-cell lung carcinoma, urothelial bladder cancer and renal cell cancer. In mice, anti-CTLA-4 therapy leads to clearance from the tumor of FOXP3⁺ regulatory T cells (T_reg cells) whose presence may impair effector T cell function.^[71]

Kinase inhibitors

Many other small molecule kinase inhibitors block the receptors for the growth factors released, including sunitinib, pazopanib, sorafenib and axitinib, all of which inhibit platelet derived growth factor receptors and VEGF receptors.^{[citation needed]}

Chimeric antigen receptor cell therapy

Chimeric antigen receptors (CAR) T cell therapy is an immunotherapy treatment that uses genetically modified T lymphocytes to effectively target tumor cells.^[72]^[73] Since the tumor microenvironment has several barriers that limit the ability of CAR T cells to infiltrate the tumor, several strategies have been developed to address this. Localized delivery of CAR T cells in glioblastoma suggested improved anti-tumor activity and engineering these cells to overexpress chemokine receptors suggested improvement of CAR T cell trafficking.^[74]

References

^ ^a ^b Alfarouk KO, Muddathir AK, Shayoub ME (January 2011). "Tumor acidity as evolutionary spite". Cancers. 3 (1): 408–414. doi:10.3390/cancers3010408. PMC 3756368. PMID 24310355.
^ "NCI Dictionary of Cancer Terms". National Cancer Institute. 2011-02-02.
^ ^a ^b ^c ^d Joyce JA, Fearon DT (April 2015). "T cell exclusion, immune privilege, and the tumor microenvironment". Science. 348 (6230): 74–80. Bibcode:2015Sci...348...74J. doi:10.1126/science.aaa6204. PMID 25838376.
^ ^a ^b ^c Spill F, Reynolds DS, Kamm RD, Zaman MH (August 2016). "Impact of the physical microenvironment on tumor progression and metastasis". Current Opinion in Biotechnology. 40: 41–48. doi:10.1016/j.copbio.2016.02.007. PMC 4975620. PMID 26938687.
^ Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.
^ Ghoshdastider U, Rohatgi N, Mojtabavi Naeini M, Baruah P, Revkov E, Guo YA, et al. (April 2021). "Pan-Cancer Analysis of Ligand-Receptor Cross-talk in the Tumor Microenvironment". Cancer Research. 81 (7): 1802–1812. doi:10.1158/0008-5472.CAN-20-2352. PMID 33547160. S2CID 232432582.
^ Žavbi J, Breznik B (2021). "Modelling the microenvironment of the most aggressive brain tumours for preclinical studies". Advances in Cancer Biology - Metastasis. 3: 100017. doi:10.1016/j.adcanc.2021.100017. ISSN 2667-3940. S2CID 244452599.
^ The Lancet, Volume 133, Issue 3421, 23 March 1889, Pages 571-573
^ Halachmi E, Witz IP (May 1989). "Differential tumorigenicity of 3T3 cells transformed in vitro with polyoma virus and in vivo selection for high tumorigenicity" (PDF). Cancer Research. 49 (9): 2383–2389. PMID 2539901.
^ Witz IP, Levy-Nissenbaum O (October 2006). "The tumor microenvironment in the post-PAGET era". Cancer Letters. 242 (1): 1–10. doi:10.1016/j.canlet.2005.12.005. PMID 16413116.
^ Al-Ostoot, Fares Hezam; Salah, Salma; Khamees, Hussien Ahmed; Khanum, Shaukath Ara (2021-01-01). "Tumor angiogenesis: Current challenges and therapeutic opportunities". Cancer Treatment and Research Communications. 28: 100422. doi:10.1016/j.ctarc.2021.100422. ISSN 2468-2942. PMID 34147821.
^ ^a ^b ^c ^d Anderson, Nicole M.; Simon, M. Celeste (2020-08). "The tumor microenvironment". Current Biology. 30 (16): R921–R925. doi:10.1016/j.cub.2020.06.081. ISSN 0960-9822. PMC 8194051. PMID 32810447. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Jiang, Xianjie; Wang, Jie; Deng, Xiangying; Xiong, Fang; Zhang, Shanshan; Gong, Zhaojian; Li, Xiayu; Cao, Ke; Deng, Hao; He, Yi; Liao, Qianjin; Xiang, Bo; Zhou, Ming; Guo, Can; Zeng, Zhaoyang (2020-09-30). "The role of microenvironment in tumor angiogenesis". Journal of Experimental & Clinical Cancer Research. 39 (1): 204. doi:10.1186/s13046-020-01709-5. ISSN 1756-9966. PMC 7526376. PMID 32993787.
^ ^a ^b ^c Li, Yue; Zhao, Long; Li, Xiao-Feng (2021-08-05). "Hypoxia and the Tumor Microenvironment". Technology in Cancer Research & Treatment. 20: 15330338211036304. doi:10.1177/15330338211036304. ISSN 1533-0346. PMC 8358492. PMID 34350796.
^ Bhat, Sharath M.; Badiger, Vaishnavi A.; Vasishta, Sampara; Chakraborty, Juhi; Prasad, Seetharam; Ghosh, Sourabh; Joshi, Manjunath B. (2021-12-01). "3D tumor angiogenesis models: recent advances and challenges". Journal of Cancer Research and Clinical Oncology. 147 (12): 3477–3494. doi:10.1007/s00432-021-03814-0. ISSN 1432-1335. PMC 8557138. PMID 34613483.{{cite journal}}: CS1 maint: PMC format (link)
^ Hanahan, Douglas; Monje, Michelle (2023-03-13). "Cancer hallmarks intersect with neuroscience in the tumor microenvironment". Cancer Cell. 41 (3): 573–580. doi:10.1016/j.ccell.2023.02.012. ISSN 1535-6108. PMC 10202656. PMID 36917953.{{cite journal}}: CS1 maint: PMC format (link)
^ Alasvand, Neda; Urbanska, Aleksandra M.; Rahmati, Maryam; Saeidifar, Maryam; Gungor-Ozkerim, P. Selcan; Sefat, Farshid; Rajadas, Jayakumar; Mozafari, Masoud (2017-01-01), Grumezescu, Alexandru Mihai (ed.), "Chapter 13 - Therapeutic Nanoparticles for Targeted Delivery of Anticancer Drugs", Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics, Elsevier, pp. 245–259, doi:10.1016/b978-0-323-52725-5.00013-7, ISBN 978-0-323-52725-5, retrieved 2024-02-19
^ ^a ^b ^c ^d Danhier F, Feron O, Préat V (December 2010). "To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery". Journal of Controlled Release. 148 (2): 135–146. doi:10.1016/j.jconrel.2010.08.027. PMID 20797419.
^ ^a ^b ^c ^d ^e Weber CE, Kuo PC (September 2012). "The tumor microenvironment". Surgical Oncology. 21 (3): 172–177. doi:10.1016/j.suronc.2011.09.001. PMID 21963199.
^ Tang, Ming; Bolderson, Emma; O’Byrne, Kenneth J.; Richard, Derek J. (2021). "Tumor Hypoxia Drives Genomic Instability". Frontiers in Cell and Developmental Biology. 9. doi:10.3389/fcell.2021.626229. ISSN 2296-634X. PMC 8007910. PMID 33796526.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Wicks, Elizabeth E.; Semenza, Gregg L. (2022-06-01). "Hypoxia-inducible factors: cancer progression and clinical translation". The Journal of Clinical Investigation. 132 (11). doi:10.1172/JCI159839. ISSN 0021-9738. PMC 9151701. PMID 35642641.{{cite journal}}: CS1 maint: PMC format (link)
^ ^a ^b ^c Chen, Gaoqi; Wu, Kaiwen; Li, Hao; Xia, Demeng; He, Tianlin (2022). "Role of hypoxia in the tumor microenvironment and targeted therapy". Frontiers in Oncology. 12. doi:10.3389/fonc.2022.961637. ISSN 2234-943X. PMC 9545774. PMID 36212414.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Lee SH, Griffiths JR (June 2020). "How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH". Cancers. 12 (6): 1616. doi:10.3390/cancers12061616. PMC 7352839. PMID 32570870.
^ Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LW (July 1991). "Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts". Cancer Research. 51 (14): 3753–3761. PMID 1712249.
^ Dvorak HF (December 1986). "Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing". The New England Journal of Medicine. 315 (26): 1650–1659. doi:10.1056/NEJM198612253152606. PMID 3537791.
^ Kundu JK, Surh YJ (July–August 2008). "Inflammation: gearing the journey to cancer". Mutation Research. 659 (1–2): 15–30. doi:10.1016/j.mrrev.2008.03.002. PMID 18485806.
^ Hanahan D, Coussens LM (March 2012). "Accessories to the crime: functions of cells recruited to the tumor microenvironment". Cancer Cell. 21 (3): 309–322. doi:10.1016/j.ccr.2012.02.022. PMID 22439926.
^ Räsänen K, Vaheri A (October 2010). "Activation of fibroblasts in cancer stroma". Experimental Cell Research. 316 (17): 2713–2722. doi:10.1016/j.yexcr.2010.04.032. PMID 20451516.
^ Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. (February 2011). "Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth". Cancer Cell. 19 (2): 257–272. doi:10.1016/j.ccr.2011.01.020. PMC 3060401. PMID 21316604.
^ ^a ^b ^c Tlsty TD, Coussens LM (February 2006). "Tumor stroma and regulation of cancer development". Annual Review of Pathology. 1: 119–150. doi:10.1146/annurev.pathol.1.110304.100224. PMID 18039110.
^ Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (December 2007). "Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells". Nature Cell Biology. 9 (12): 1392–1400. doi:10.1038/ncb1658. PMID 18037882. S2CID 35445729.
^ ^a ^b Pupa SM, Ménard S, Forti S, Tagliabue E (September 2002). "New insights into the role of extracellular matrix during tumor onset and progression". Journal of Cellular Physiology. 192 (3): 259–267. doi:10.1002/jcp.10142. PMID 12124771. S2CID 31791792.
^ Montgomery AM, Reisfeld RA, Cheresh DA (September 1994). "Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen". Proceedings of the National Academy of Sciences of the United States of America. 91 (19): 8856–8860. Bibcode:1994PNAS...91.8856M. doi:10.1073/pnas.91.19.8856. PMC 44705. PMID 7522323.
^ Bergers G, Coussens LM (February 2000). "Extrinsic regulators of epithelial tumor progression: metalloproteinases". Current Opinion in Genetics & Development. 10 (1): 120–127. doi:10.1016/S0959-437X(99)00043-X. PMID 10679388.
^ Sinkus R, Lorenzen J, Schrader D, Lorenzen M, Dargatz M, Holz D (June 2000). "High-resolution tensor MR elastography for breast tumour detection". Physics in Medicine and Biology. 45 (6): 1649–1664. Bibcode:2000PMB....45.1649S. doi:10.1088/0031-9155/45/6/317. PMID 10870716. S2CID 250815945.
^ Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. (November 2009). "Matrix crosslinking forces tumor progression by enhancing integrin signaling". Cell. 139 (5): 891–906. doi:10.1016/j.cell.2009.10.027. PMC 2788004. PMID 19931152.
^ Mantovani A, Allavena P, Sica A, Balkwill F (July 2008). "Cancer-related inflammation". Nature. 454 (7203): 436–444. Bibcode:2008Natur.454..436M. doi:10.1038/nature07205. hdl:2434/145688. PMID 18650914. S2CID 4429118.
^ ^a ^b Mathias RA, Gopal SK, Simpson RJ (January 2013). "Contribution of cells undergoing epithelial-mesenchymal transition to the tumour microenvironment". Journal of Proteomics. 78: 545–557. doi:10.1016/j.jprot.2012.10.016. PMID 23099347.
^ ^a ^b Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (April 2007). "Tumor-released microvesicles as vehicles of immunosuppression". Cancer Research. 67 (7): 2912–2915. doi:10.1158/0008-5472.CAN-07-0520. PMID 17409393.
^ Balkwill F, Charles KA, Mantovani A (March 2005). "Smoldering and polarized inflammation in the initiation and promotion of malignant disease". Cancer Cell. 7 (3): 211–217. doi:10.1016/j.ccr.2005.02.013. PMID 15766659.
^ Qian BZ, Pollard JW (April 2010). "Macrophage diversity enhances tumor progression and metastasis". Cell. 141 (1): 39–51. doi:10.1016/j.cell.2010.03.014. PMC 4994190. PMID 20371344.
^ ^a ^b Solinas G, Germano G, Mantovani A, Allavena P (November 2009). "Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation". Journal of Leukocyte Biology. 86 (5): 1065–1073. doi:10.1189/jlb.0609385. hdl:2318/1740263. PMID 19741157. S2CID 6573469.
^ Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. (March 2006). "A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)". Blood. 107 (5): 2112–2122. doi:10.1182/blood-2005-01-0428. PMID 16269622. S2CID 5884781.
^ Zhang W, Wang L, Zhou D, Cui Q, Zhao D, Wu Y (January 2011). "Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified". Leukemia & Lymphoma. 52 (1): 46–52. doi:10.3109/10428194.2010.529204. PMID 21077742. S2CID 26116121.
^ Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF (December 2011). "Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma". Medical Oncology. 28 (4): 1447–1452. doi:10.1007/s12032-010-9638-5. PMID 20676804. S2CID 24840259.
^ Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. (September 2011). "Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells". Molecular Cancer. 10 (117): 117. doi:10.1186/1476-4598-10-117. PMC 3190352. PMID 21939504.
^ Coffelt SB, Wellenstein MD, de Visser KE (July 2016). "Neutrophils in cancer: neutral no more" (PDF). Nature Reviews. Cancer. 16 (7): 431–446. doi:10.1038/nrc.2016.52. PMID 27282249. S2CID 4393159.
^ ^a ^b Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. (August 2015). "The prognostic landscape of genes and infiltrating immune cells across human cancers". Nature Medicine. 21 (8): 938–945. doi:10.1038/nm.3909. PMC 4852857. PMID 26193342.
^ Engblom C, Pfirschke C, Pittet MJ (July 2016). "The role of myeloid cells in cancer therapies". Nature Reviews. Cancer. 16 (7): 447–462. doi:10.1038/nrc.2016.54. PMID 27339708. S2CID 21924175.
^ Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, et al. (February 2015). "Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status". Cancer. 121 (4): 545–555. doi:10.1002/cncr.29100. PMID 25336438. S2CID 926930.
^ Jiang L, Jiang S, Situ D, Lin Y, Yang H, Li Y, et al. (April 2015). "Prognostic value of monocyte and neutrophils to lymphocytes ratio in patients with metastatic soft tissue sarcoma". Oncotarget. 6 (11): 9542–9550. doi:10.18632/oncotarget.3283. PMC 4496237. PMID 25865224.
^ Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, et al. (March 2014). "Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients". Proceedings of the National Academy of Sciences of the United States of America. 111 (11): 4221–4226. Bibcode:2014PNAS..111.4221W. doi:10.1073/pnas.1320753111. PMC 3964061. PMID 24591638.
^ Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. (June 2015). "IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis". Nature. 522 (7556): 345–348. Bibcode:2015Natur.522..345C. doi:10.1038/nature14282. PMC 4475637. PMID 25822788.
^ ^a ^b Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, et al. (December 2017). "Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils". Science. 358 (6367): eaal5081. doi:10.1126/science.aal5081. PMC 6343476. PMID 29191879.
^ Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. (February 2015). "Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils". Proceedings of the National Academy of Sciences of the United States of America. 112 (6): E566–E575. Bibcode:2015PNAS..112E.566C. doi:10.1073/pnas.1424927112. PMC 4330753. PMID 25624500.
^ Wculek SK, Malanchi I (December 2015). "Neutrophils support lung colonization of metastasis-initiating breast cancer cells". Nature. 528 (7582): 413–417. Bibcode:2015Natur.528..413W. doi:10.1038/nature16140. PMC 4700594. PMID 26649828.
^ Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S, Thompson AA, et al. (June 2015). "MET is required for the recruitment of anti-tumoural neutrophils". Nature. 522 (7556): 349–353. Bibcode:2015Natur.522..349F. doi:10.1038/nature14407. PMC 4594765. PMID 25985180.
^ Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (September 2011). "Tumor entrained neutrophils inhibit seeding in the premetastatic lung". Cancer Cell. 20 (3): 300–314. doi:10.1016/j.ccr.2011.08.012. PMC 3172582. PMID 21907922.
^ Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. (September 2009). "Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN". Cancer Cell. 16 (3): 183–194. doi:10.1016/j.ccr.2009.06.017. PMC 2754404. PMID 19732719.
^ Turcotte S, Rosenberg SA (2011). "Immunotherapy for metastatic solid cancers". Advances in Surgery. 45: 341–360. doi:10.1016/j.yasu.2011.04.003. PMC 3578602. PMID 21954698.
^ Clayton A, Tabi Z (May–June 2005). "Exosomes and the MICA-NKG2D system in cancer". Blood Cells, Molecules & Diseases. 34 (3): 206–213. doi:10.1016/j.bcmd.2005.03.003. PMID 15885603.
^ Plitas G, Rudensky AY (March 2020). "Regulatory T Cells in Cancer". Annual Review of Cancer Biology. 4: 459–77. doi:10.1146/annurev-cancerbio-030419-033428.
^ Freedman LP, Gibson MC, Ethier SP, Soule HR, Neve RM, Reid YA (June 2015). "Reproducibility: changing the policies and culture of cell line authentication". Nature Methods. 12 (6): 493–497. doi:10.1038/nmeth.3403. PMID 26020501. S2CID 20557369.
^ Franchi-Mendes T, Eduardo R, Domenici G, Brito C (September 2021). "3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment". Cancers. 13 (18): 4610. doi:10.3390/cancers13184610. PMC 8468887. PMID 34572836.
^ Feng Y, Liao Z, Zhang H, Xie X, You F, Liao X, et al. (January 2023). "Emerging nanomedicines strategies focused on tumor microenvironment against cancer recurrence and metastasis". Chemical Engineering Journal. 452: 139506. doi:10.1016/j.cej.2022.139506. S2CID 252676223.
^ Raju GS, Pavitra E, Varaprasad GL, Bandaru SS, Nagaraju GP, Farran B, et al. (June 2022). "Nanoparticles mediated tumor microenvironment modulation: current advances and applications". Journal of Nanobiotechnology. 20 (1): 274. doi:10.1186/s12951-022-01476-9. PMC 9195263. PMID 35701781.
^ Unezaki S, Maruyama K, Hosoda JI, Nagae I, Koyanagi Y, Nakata M, Ishida O, Iwatsuru M, Tsuchiya S (22 November 1996). "Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy". International Journal of Pharmaceutics. 144 (1): 11–17. doi:10.1016/S0378-5173(96)04674-1.
^ Lilavivat S, Sardar D, Jana S, Thomas GC, Woycechowsky KJ (August 2012). "In vivo encapsulation of nucleic acids using an engineered nonviral protein capsid". Journal of the American Chemical Society. 134 (32): 13152–13155. doi:10.1021/ja302743g. PMID 22827162.
^ Ramishetti S, Huang L (December 2012). "Intelligent design of multifunctional lipid-coated nanoparticle platforms for cancer therapy". Therapeutic Delivery. 3 (12): 1429–1445. doi:10.4155/tde.12.127. PMC 3584330. PMID 23323560.
^ Jain RK (June 1987). "Transport of molecules in the tumor interstitium: a review". Cancer Research. 47 (12): 3039–3051. PMID 3555767.
^ Li C, Jiang P, Wei S, Xu X, Wang J (July 2020). "Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects". Molecular Cancer. 19 (1): 116. doi:10.1186/s12943-020-01234-1. PMC 7367382. PMID 32680511.
^ Sadelain M, Rivière I, Brentjens R (January 2003). "Targeting tumours with genetically enhanced T lymphocytes". Nature Reviews. Cancer. 3 (1): 35–45. doi:10.1038/nrc971. PMID 12509765. S2CID 33707802.
^ Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL, Kenderian SS (June 2022). "CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities". Molecular Therapy Oncolytics. 25: 69–77. doi:10.1016/j.omto.2022.03.009. PMC 8980704. PMID 35434273.
^ Brown CE, Aguilar B, Starr R, Yang X, Chang WC, Weng L, et al. (January 2018). "Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma". Molecular Therapy. 26 (1): 31–44. doi:10.1016/j.ymthe.2017.10.002. PMC 5763077. PMID 29103912.

[Tumor_acidity_as_evolutionary_spite-1] Alfarouk KO, Muddathir AK, Shayoub ME (January 2011). "Tumor acidity as evolutionary spite". Cancers. 3 (1): 408–414. doi:10.3390/cancers3010408. PMC 3756368. PMID 24310355.

[2] "NCI Dictionary of Cancer Terms". National Cancer Institute. 2011-02-02.

[Joyce_2015-3] Joyce JA, Fearon DT (April 2015). "T cell exclusion, immune privilege, and the tumor microenvironment". Science. 348 (6230): 74–80. Bibcode:2015Sci...348...74J. doi:10.1126/science.aaa6204. PMID 25838376.

[physicalMicroenvironment-4] Spill F, Reynolds DS, Kamm RD, Zaman MH (August 2016). "Impact of the physical microenvironment on tumor progression and metastasis". Current Opinion in Biotechnology. 40: 41–48. doi:10.1016/j.copbio.2016.02.007. PMC 4975620. PMID 26938687.

[5] Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.

[pmid33547160-6] Ghoshdastider U, Rohatgi N, Mojtabavi Naeini M, Baruah P, Revkov E, Guo YA, et al. (April 2021). "Pan-Cancer Analysis of Ligand-Receptor Cross-talk in the Tumor Microenvironment". Cancer Research. 81 (7): 1802–1812. doi:10.1158/0008-5472.CAN-20-2352. PMID 33547160. S2CID 232432582.

[Žavbi_2021-7] Žavbi J, Breznik B (2021). "Modelling the microenvironment of the most aggressive brain tumours for preclinical studies". Advances in Cancer Biology - Metastasis. 3: 100017. doi:10.1016/j.adcanc.2021.100017. ISSN 2667-3940. S2CID 244452599.

[8] The Lancet, Volume 133, Issue 3421, 23 March 1889, Pages 571-573

[9] Halachmi E, Witz IP (May 1989). "Differential tumorigenicity of 3T3 cells transformed in vitro with polyoma virus and in vivo selection for high tumorigenicity" (PDF). Cancer Research. 49 (9): 2383–2389. PMID 2539901.

[Witz-10] Witz IP, Levy-Nissenbaum O (October 2006). "The tumor microenvironment in the post-PAGET era". Cancer Letters. 242 (1): 1–10. doi:10.1016/j.canlet.2005.12.005. PMID 16413116.

[11] Al-Ostoot, Fares Hezam; Salah, Salma; Khamees, Hussien Ahmed; Khanum, Shaukath Ara (2021-01-01). "Tumor angiogenesis: Current challenges and therapeutic opportunities". Cancer Treatment and Research Communications. 28: 100422. doi:10.1016/j.ctarc.2021.100422. ISSN 2468-2942. PMID 34147821.

[:1-12] Anderson, Nicole M.; Simon, M. Celeste (2020-08). "The tumor microenvironment". Current Biology. 30 (16): R921–R925. doi:10.1016/j.cub.2020.06.081. ISSN 0960-9822. PMC 8194051. PMID 32810447. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:0-13] Jiang, Xianjie; Wang, Jie; Deng, Xiangying; Xiong, Fang; Zhang, Shanshan; Gong, Zhaojian; Li, Xiayu; Cao, Ke; Deng, Hao; He, Yi; Liao, Qianjin; Xiang, Bo; Zhou, Ming; Guo, Can; Zeng, Zhaoyang (2020-09-30). "The role of microenvironment in tumor angiogenesis". Journal of Experimental & Clinical Cancer Research. 39 (1): 204. doi:10.1186/s13046-020-01709-5. ISSN 1756-9966. PMC 7526376. PMID 32993787.

[:2-14] Li, Yue; Zhao, Long; Li, Xiao-Feng (2021-08-05). "Hypoxia and the Tumor Microenvironment". Technology in Cancer Research & Treatment. 20: 15330338211036304. doi:10.1177/15330338211036304. ISSN 1533-0346. PMC 8358492. PMID 34350796.

[15] Bhat, Sharath M.; Badiger, Vaishnavi A.; Vasishta, Sampara; Chakraborty, Juhi; Prasad, Seetharam; Ghosh, Sourabh; Joshi, Manjunath B. (2021-12-01). "3D tumor angiogenesis models: recent advances and challenges". Journal of Cancer Research and Clinical Oncology. 147 (12): 3477–3494. doi:10.1007/s00432-021-03814-0. ISSN 1432-1335. PMC 8557138. PMID 34613483.{{cite journal}}: CS1 maint: PMC format (link)

[16] Hanahan, Douglas; Monje, Michelle (2023-03-13). "Cancer hallmarks intersect with neuroscience in the tumor microenvironment". Cancer Cell. 41 (3): 573–580. doi:10.1016/j.ccell.2023.02.012. ISSN 1535-6108. PMC 10202656. PMID 36917953.{{cite journal}}: CS1 maint: PMC format (link)

[17] Alasvand, Neda; Urbanska, Aleksandra M.; Rahmati, Maryam; Saeidifar, Maryam; Gungor-Ozkerim, P. Selcan; Sefat, Farshid; Rajadas, Jayakumar; Mozafari, Masoud (2017-01-01), Grumezescu, Alexandru Mihai (ed.), "Chapter 13 - Therapeutic Nanoparticles for Targeted Delivery of Anticancer Drugs", Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics, Elsevier, pp. 245–259, doi:10.1016/b978-0-323-52725-5.00013-7, ISBN 978-0-323-52725-5, retrieved 2024-02-19

[Danhier-18] Danhier F, Feron O, Préat V (December 2010). "To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery". Journal of Controlled Release. 148 (2): 135–146. doi:10.1016/j.jconrel.2010.08.027. PMID 20797419.

[Weber-19] Weber CE, Kuo PC (September 2012). "The tumor microenvironment". Surgical Oncology. 21 (3): 172–177. doi:10.1016/j.suronc.2011.09.001. PMID 21963199.

[20] Tang, Ming; Bolderson, Emma; O’Byrne, Kenneth J.; Richard, Derek J. (2021). "Tumor Hypoxia Drives Genomic Instability". Frontiers in Cell and Developmental Biology. 9. doi:10.3389/fcell.2021.626229. ISSN 2296-634X. PMC 8007910. PMID 33796526.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[21] Wicks, Elizabeth E.; Semenza, Gregg L. (2022-06-01). "Hypoxia-inducible factors: cancer progression and clinical translation". The Journal of Clinical Investigation. 132 (11). doi:10.1172/JCI159839. ISSN 0021-9738. PMC 9151701. PMID 35642641.{{cite journal}}: CS1 maint: PMC format (link)

[:3-22] Chen, Gaoqi; Wu, Kaiwen; Li, Hao; Xia, Demeng; He, Tianlin (2022). "Role of hypoxia in the tumor microenvironment and targeted therapy". Frontiers in Oncology. 12. doi:10.3389/fonc.2022.961637. ISSN 2234-943X. PMC 9545774. PMID 36212414.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[23] Lee SH, Griffiths JR (June 2020). "How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH". Cancers. 12 (6): 1616. doi:10.3390/cancers12061616. PMC 7352839. PMID 32570870.

[24] Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LW (July 1991). "Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts". Cancer Research. 51 (14): 3753–3761. PMID 1712249.

[Dvorak-25] Dvorak HF (December 1986). "Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing". The New England Journal of Medicine. 315 (26): 1650–1659. doi:10.1056/NEJM198612253152606. PMID 3537791.

[26] Kundu JK, Surh YJ (July–August 2008). "Inflammation: gearing the journey to cancer". Mutation Research. 659 (1–2): 15–30. doi:10.1016/j.mrrev.2008.03.002. PMID 18485806.

[Hanahan-27] Hanahan D, Coussens LM (March 2012). "Accessories to the crime: functions of cells recruited to the tumor microenvironment". Cancer Cell. 21 (3): 309–322. doi:10.1016/j.ccr.2012.02.022. PMID 22439926.

[28] Räsänen K, Vaheri A (October 2010). "Activation of fibroblasts in cancer stroma". Experimental Cell Research. 316 (17): 2713–2722. doi:10.1016/j.yexcr.2010.04.032. PMID 20451516.

[29] Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. (February 2011). "Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth". Cancer Cell. 19 (2): 257–272. doi:10.1016/j.ccr.2011.01.020. PMC 3060401. PMID 21316604.

[Tisty-30] Tlsty TD, Coussens LM (February 2006). "Tumor stroma and regulation of cancer development". Annual Review of Pathology. 1: 119–150. doi:10.1146/annurev.pathol.1.110304.100224. PMID 18039110.

[31] Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (December 2007). "Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells". Nature Cell Biology. 9 (12): 1392–1400. doi:10.1038/ncb1658. PMID 18037882. S2CID 35445729.

[Pupa-32] Pupa SM, Ménard S, Forti S, Tagliabue E (September 2002). "New insights into the role of extracellular matrix during tumor onset and progression". Journal of Cellular Physiology. 192 (3): 259–267. doi:10.1002/jcp.10142. PMID 12124771. S2CID 31791792.

[33] Montgomery AM, Reisfeld RA, Cheresh DA (September 1994). "Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen". Proceedings of the National Academy of Sciences of the United States of America. 91 (19): 8856–8860. Bibcode:1994PNAS...91.8856M. doi:10.1073/pnas.91.19.8856. PMC 44705. PMID 7522323.

[34] Bergers G, Coussens LM (February 2000). "Extrinsic regulators of epithelial tumor progression: metalloproteinases". Current Opinion in Genetics & Development. 10 (1): 120–127. doi:10.1016/S0959-437X(99)00043-X. PMID 10679388.

[35] Sinkus R, Lorenzen J, Schrader D, Lorenzen M, Dargatz M, Holz D (June 2000). "High-resolution tensor MR elastography for breast tumour detection". Physics in Medicine and Biology. 45 (6): 1649–1664. Bibcode:2000PMB....45.1649S. doi:10.1088/0031-9155/45/6/317. PMID 10870716. S2CID 250815945.

[Levental-36] Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. (November 2009). "Matrix crosslinking forces tumor progression by enhancing integrin signaling". Cell. 139 (5): 891–906. doi:10.1016/j.cell.2009.10.027. PMC 2788004. PMID 19931152.

[37] Mantovani A, Allavena P, Sica A, Balkwill F (July 2008). "Cancer-related inflammation". Nature. 454 (7203): 436–444. Bibcode:2008Natur.454..436M. doi:10.1038/nature07205. hdl:2434/145688. PMID 18650914. S2CID 4429118.

[Mathias-38] Mathias RA, Gopal SK, Simpson RJ (January 2013). "Contribution of cells undergoing epithelial-mesenchymal transition to the tumour microenvironment". Journal of Proteomics. 78: 545–557. doi:10.1016/j.jprot.2012.10.016. PMID 23099347.

[Valenti-39] Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (April 2007). "Tumor-released microvesicles as vehicles of immunosuppression". Cancer Research. 67 (7): 2912–2915. doi:10.1158/0008-5472.CAN-07-0520. PMID 17409393.

[40] Balkwill F, Charles KA, Mantovani A (March 2005). "Smoldering and polarized inflammation in the initiation and promotion of malignant disease". Cancer Cell. 7 (3): 211–217. doi:10.1016/j.ccr.2005.02.013. PMID 15766659.

[41] Qian BZ, Pollard JW (April 2010). "Macrophage diversity enhances tumor progression and metastasis". Cell. 141 (1): 39–51. doi:10.1016/j.cell.2010.03.014. PMC 4994190. PMID 20371344.

[Solinas-42] Solinas G, Germano G, Mantovani A, Allavena P (November 2009). "Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation". Journal of Leukocyte Biology. 86 (5): 1065–1073. doi:10.1189/jlb.0609385. hdl:2318/1740263. PMID 19741157. S2CID 6573469.

[43] Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. (March 2006). "A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)". Blood. 107 (5): 2112–2122. doi:10.1182/blood-2005-01-0428. PMID 16269622. S2CID 5884781.

[44] Zhang W, Wang L, Zhou D, Cui Q, Zhao D, Wu Y (January 2011). "Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified". Leukemia & Lymphoma. 52 (1): 46–52. doi:10.3109/10428194.2010.529204. PMID 21077742. S2CID 26116121.

[45] Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF (December 2011). "Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma". Medical Oncology. 28 (4): 1447–1452. doi:10.1007/s12032-010-9638-5. PMID 20676804. S2CID 24840259.

[46] Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. (September 2011). "Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells". Molecular Cancer. 10 (117): 117. doi:10.1186/1476-4598-10-117. PMC 3190352. PMID 21939504.

[47] Coffelt SB, Wellenstein MD, de Visser KE (July 2016). "Neutrophils in cancer: neutral no more" (PDF). Nature Reviews. Cancer. 16 (7): 431–446. doi:10.1038/nrc.2016.52. PMID 27282249. S2CID 4393159.

[Gentles_2015-48] Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. (August 2015). "The prognostic landscape of genes and infiltrating immune cells across human cancers". Nature Medicine. 21 (8): 938–945. doi:10.1038/nm.3909. PMC 4852857. PMID 26193342.

[49] Engblom C, Pfirschke C, Pittet MJ (July 2016). "The role of myeloid cells in cancer therapies". Nature Reviews. Cancer. 16 (7): 447–462. doi:10.1038/nrc.2016.54. PMID 27339708. S2CID 21924175.

[50] Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, et al. (February 2015). "Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status". Cancer. 121 (4): 545–555. doi:10.1002/cncr.29100. PMID 25336438. S2CID 926930.

[51] Jiang L, Jiang S, Situ D, Lin Y, Yang H, Li Y, et al. (April 2015). "Prognostic value of monocyte and neutrophils to lymphocytes ratio in patients with metastatic soft tissue sarcoma". Oncotarget. 6 (11): 9542–9550. doi:10.18632/oncotarget.3283. PMC 4496237. PMID 25865224.

[52] Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, et al. (March 2014). "Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients". Proceedings of the National Academy of Sciences of the United States of America. 111 (11): 4221–4226. Bibcode:2014PNAS..111.4221W. doi:10.1073/pnas.1320753111. PMC 3964061. PMID 24591638.

[53] Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. (June 2015). "IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis". Nature. 522 (7556): 345–348. Bibcode:2015Natur.522..345C. doi:10.1038/nature14282. PMC 4475637. PMID 25822788.

[high_neutrophils-54] Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, et al. (December 2017). "Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils". Science. 358 (6367): eaal5081. doi:10.1126/science.aal5081. PMC 6343476. PMID 29191879.

[55] Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. (February 2015). "Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils". Proceedings of the National Academy of Sciences of the United States of America. 112 (6): E566–E575. Bibcode:2015PNAS..112E.566C. doi:10.1073/pnas.1424927112. PMC 4330753. PMID 25624500.

[56] Wculek SK, Malanchi I (December 2015). "Neutrophils support lung colonization of metastasis-initiating breast cancer cells". Nature. 528 (7582): 413–417. Bibcode:2015Natur.528..413W. doi:10.1038/nature16140. PMC 4700594. PMID 26649828.

[57] Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S, Thompson AA, et al. (June 2015). "MET is required for the recruitment of anti-tumoural neutrophils". Nature. 522 (7556): 349–353. Bibcode:2015Natur.522..349F. doi:10.1038/nature14407. PMC 4594765. PMID 25985180.

[58] Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (September 2011). "Tumor entrained neutrophils inhibit seeding in the premetastatic lung". Cancer Cell. 20 (3): 300–314. doi:10.1016/j.ccr.2011.08.012. PMC 3172582. PMID 21907922.

[59] Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. (September 2009). "Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN". Cancer Cell. 16 (3): 183–194. doi:10.1016/j.ccr.2009.06.017. PMC 2754404. PMID 19732719.

[60] Turcotte S, Rosenberg SA (2011). "Immunotherapy for metastatic solid cancers". Advances in Surgery. 45: 341–360. doi:10.1016/j.yasu.2011.04.003. PMC 3578602. PMID 21954698.

[61] Clayton A, Tabi Z (May–June 2005). "Exosomes and the MICA-NKG2D system in cancer". Blood Cells, Molecules & Diseases. 34 (3): 206–213. doi:10.1016/j.bcmd.2005.03.003. PMID 15885603.

[62] Plitas G, Rudensky AY (March 2020). "Regulatory T Cells in Cancer". Annual Review of Cancer Biology. 4: 459–77. doi:10.1146/annurev-cancerbio-030419-033428.

[63] Freedman LP, Gibson MC, Ethier SP, Soule HR, Neve RM, Reid YA (June 2015). "Reproducibility: changing the policies and culture of cell line authentication". Nature Methods. 12 (6): 493–497. doi:10.1038/nmeth.3403. PMID 26020501. S2CID 20557369.

[64] Franchi-Mendes T, Eduardo R, Domenici G, Brito C (September 2021). "3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment". Cancers. 13 (18): 4610. doi:10.3390/cancers13184610. PMC 8468887. PMID 34572836.

[65] Feng Y, Liao Z, Zhang H, Xie X, You F, Liao X, et al. (January 2023). "Emerging nanomedicines strategies focused on tumor microenvironment against cancer recurrence and metastasis". Chemical Engineering Journal. 452: 139506. doi:10.1016/j.cej.2022.139506. S2CID 252676223.

[66] Raju GS, Pavitra E, Varaprasad GL, Bandaru SS, Nagaraju GP, Farran B, et al. (June 2022). "Nanoparticles mediated tumor microenvironment modulation: current advances and applications". Journal of Nanobiotechnology. 20 (1): 274. doi:10.1186/s12951-022-01476-9. PMC 9195263. PMID 35701781.

[67] Unezaki S, Maruyama K, Hosoda JI, Nagae I, Koyanagi Y, Nakata M, Ishida O, Iwatsuru M, Tsuchiya S (22 November 1996). "Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy". International Journal of Pharmaceutics. 144 (1): 11–17. doi:10.1016/S0378-5173(96)04674-1.

[68] Lilavivat S, Sardar D, Jana S, Thomas GC, Woycechowsky KJ (August 2012). "In vivo encapsulation of nucleic acids using an engineered nonviral protein capsid". Journal of the American Chemical Society. 134 (32): 13152–13155. doi:10.1021/ja302743g. PMID 22827162.

[69] Ramishetti S, Huang L (December 2012). "Intelligent design of multifunctional lipid-coated nanoparticle platforms for cancer therapy". Therapeutic Delivery. 3 (12): 1429–1445. doi:10.4155/tde.12.127. PMC 3584330. PMID 23323560.

[70] Jain RK (June 1987). "Transport of molecules in the tumor interstitium: a review". Cancer Research. 47 (12): 3039–3051. PMID 3555767.

[71] Li C, Jiang P, Wei S, Xu X, Wang J (July 2020). "Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects". Molecular Cancer. 19 (1): 116. doi:10.1186/s12943-020-01234-1. PMC 7367382. PMID 32680511.

[72] Sadelain M, Rivière I, Brentjens R (January 2003). "Targeting tumours with genetically enhanced T lymphocytes". Nature Reviews. Cancer. 3 (1): 35–45. doi:10.1038/nrc971. PMID 12509765. S2CID 33707802.

[73] Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL, Kenderian SS (June 2022). "CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities". Molecular Therapy Oncolytics. 25: 69–77. doi:10.1016/j.omto.2022.03.009. PMC 8980704. PMID 35434273.

[74] Brown CE, Aguilar B, Starr R, Yang X, Chang WC, Weng L, et al. (January 2018). "Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma". Molecular Therapy. 26 (1): 31–44. doi:10.1016/j.ymthe.2017.10.002. PMC 5763077. PMID 29103912.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

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[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

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@@ Line 16: / Line 16: @@
 == Vasculature ==
-A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor.<ref>{{Cite journal |last1=Al-Ostoot |first1=Fares Hezam |last2=Salah |first2=Salma |last3=Khamees |first3=Hussien Ahmed |last4=Khanum |first4=Shaukath Ara |date=2021-01-01 |title=Tumor angiogenesis: Current challenges and therapeutic opportunities |url=https://www.sciencedirect.com/science/article/pii/S2468294221001209 |journal=Cancer Treatment and Research Communications |volume=28 |pages=100422 |doi=10.1016/j.ctarc.2021.100422 |pmid=34147821 |issn=2468-2942|doi-access=free }}</ref> 80–90% of cancer are [[carcinoma]]s, or cancers that form from [[Epithelium|epithelial tissue]].<ref>{{Cite web |title=Cancer Classification {{!}} SEER Training |url=https://training.seer.cancer.gov/disease/categories/classification.html |access-date=2024-02-08 |website=training.seer.cancer.gov}}</ref> This tissue is not vascularized, and without proper vasculization a tumor cannot grow greater than 1-2 mm in diameter.<ref>{{Cite web |date=2021-05-18 |title=5.2: Epithelial Tissues |url=https://bio.libretexts.org/Courses/West_Hills_College_-_Lemoore/Human_Anatomy_Laboratory_Manual_(Hartline)/05%3A_Tissues/5.02%3A_Epithelial_Tissues |access-date=2024-02-08 |website=Biology LibreTexts |language=en}}</ref><ref name=":0">{{Cite journal |last1=Jiang |first1=Xianjie |last2=Wang |first2=Jie |last3=Deng |first3=Xiangying |last4=Xiong |first4=Fang |last5=Zhang |first5=Shanshan |last6=Gong |first6=Zhaojian |last7=Li |first7=Xiayu |last8=Cao |first8=Ke |last9=Deng |first9=Hao |last10=He |first10=Yi |last11=Liao |first11=Qianjin |last12=Xiang |first12=Bo |last13=Zhou |first13=Ming |last14=Guo |first14=Can |last15=Zeng |first15=Zhaoyang |date=2020-09-30 |title=The role of microenvironment in tumor angiogenesis |journal=Journal of Experimental & Clinical Cancer Research |volume=39 |issue=1 |pages=204 |doi=10.1186/s13046-020-01709-5 |doi-access=free |issn=1756-9966 |pmc=7526376 |pmid=32993787}}</ref> [[Angiogenesis]], a prossess where new blood vessels emerge from pre-existing vasculature, is upregulated to feed the cancer cells, and is linked to tumor malignancy.<ref name=":0" /> As a result the vasculature formed in the tumor microenvironment differs from that of normal tissue. The blood vessels formed are often tortuous, with a compromised blood flow.<ref>{{Cite journal |last1=Bhat |first1=Sharath M. |last2=Badiger |first2=Vaishnavi A. |last3=Vasishta |first3=Sampara |last4=Chakraborty |first4=Juhi |last5=Prasad |first5=Seetharam |last6=Ghosh |first6=Sourabh |last7=Joshi |first7=Manjunath B. |date=2021-12-01 |title=3D tumor angiogenesis models: recent advances and challenges |url=https://doi.org/10.1007/s00432-021-03814-0 |journal=Journal of Cancer Research and Clinical Oncology |language=en |volume=147 |issue=12 |pages=3477–3494 |doi=10.1007/s00432-021-03814-0 |issn=1432-1335 |pmc=8557138 |pmid=34613483}}</ref>
+A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor.<ref>{{Cite journal |last1=Al-Ostoot |first1=Fares Hezam |last2=Salah |first2=Salma |last3=Khamees |first3=Hussien Ahmed |last4=Khanum |first4=Shaukath Ara |date=2021-01-01 |title=Tumor angiogenesis: Current challenges and therapeutic opportunities |url=https://www.sciencedirect.com/science/article/pii/S2468294221001209 |journal=Cancer Treatment and Research Communications |volume=28 |pages=100422 |doi=10.1016/j.ctarc.2021.100422 |issn=2468-2942 |pmid=34147821 |doi-access=free}}</ref> Tumors smaller than 1-2 mm in diameter are delivered oxygen and nutrients through [[passive diffusion]]. In larger tumors the center becomes too far away from the existing blood supply, leading the tumor microenvironment to become hypoxic and acidic.<ref name=":1">{{Cite journal |last=Anderson |first=Nicole M. |last2=Simon |first2=M. Celeste |date=2020-08 |title=The tumor microenvironment |url=https://doi.org/10.1016/j.cub.2020.06.081 |journal=Current Biology |volume=30 |issue=16 |pages=R921–R925 |doi=10.1016/j.cub.2020.06.081 |issn=0960-9822 |pmc=PMC8194051 |pmid=32810447}}</ref> [[Angiogenesis]] is upregulated to feed the cancer cells and is linked to tumor malignancy.<ref name=":0">{{Cite journal |last1=Jiang |first1=Xianjie |last2=Wang |first2=Jie |last3=Deng |first3=Xiangying |last4=Xiong |first4=Fang |last5=Zhang |first5=Shanshan |last6=Gong |first6=Zhaojian |last7=Li |first7=Xiayu |last8=Cao |first8=Ke |last9=Deng |first9=Hao |last10=He |first10=Yi |last11=Liao |first11=Qianjin |last12=Xiang |first12=Bo |last13=Zhou |first13=Ming |last14=Guo |first14=Can |last15=Zeng |first15=Zhaoyang |date=2020-09-30 |title=The role of microenvironment in tumor angiogenesis |journal=Journal of Experimental & Clinical Cancer Research |volume=39 |issue=1 |pages=204 |doi=10.1186/s13046-020-01709-5 |issn=1756-9966 |pmc=7526376 |pmid=32993787 |doi-access=free}}</ref>
-=== Enhanced permeability and retention effect ===
+=== Endothelial cells and angiogenesis ===
+In hypoxic environments the tissue sends out signals called [[Hypoxia-inducible factor|hypoxia inducible factors]] (HIFs) that can stimulate nearby [[Endothelium|endothelial cells]] to secrete factors such as [[vascular endothelial growth factor]] (VEGF). VEGF activates the endothelial cells, which begins the process of [[angiogenesis]], where new blood vessels emerge from pre-existing vasculature.<ref name=":2">{{Cite journal |last=Li |first=Yue |last2=Zhao |first2=Long |last3=Li |first3=Xiao-Feng |date=2021-08-05 |title=Hypoxia and the Tumor Microenvironment |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358492/ |journal=Technology in Cancer Research & Treatment |volume=20 |pages=15330338211036304 |doi=10.1177/15330338211036304 |issn=1533-0346 |pmc=8358492 |pmid=34350796}}</ref> The blood vessel formed in the tumor environment often doesn’t mature properly, and as a result the vasculature formed in the tumor microenvironment differs from that of normal tissue. The blood vessels formed are often “leaky” and tortuous, with a compromised blood flow.<ref>{{Cite journal |last=Bhat |first=Sharath M. |last2=Badiger |first2=Vaishnavi A. |last3=Vasishta |first3=Sampara |last4=Chakraborty |first4=Juhi |last5=Prasad |first5=Seetharam |last6=Ghosh |first6=Sourabh |last7=Joshi |first7=Manjunath B. |date=2021-12-01 |title=3D tumor angiogenesis models: recent advances and challenges |url=https://doi.org/10.1007/s00432-021-03814-0 |journal=Journal of Cancer Research and Clinical Oncology |language=en |volume=147 |issue=12 |pages=3477–3494 |doi=10.1007/s00432-021-03814-0 |issn=1432-1335 |pmc=PMC8557138 |pmid=34613483}}</ref><ref name=":1" /> As tumors cannot grow large without proper vasculature, sustained angiogenesis is therefore considered one of the hallmarks of cancer.<ref>{{Cite journal |last=Hanahan |first=Douglas |last2=Monje |first2=Michelle |date=2023-03-13 |title=Cancer hallmarks intersect with neuroscience in the tumor microenvironment |url=https://doi.org/10.1016/j.ccell.2023.02.012 |journal=Cancer Cell |volume=41 |issue=3 |pages=573–580 |doi=10.1016/j.ccell.2023.02.012 |issn=1535-6108 |pmc=PMC10202656 |pmid=36917953}}</ref>
+In later stages of tumor progression endothelial cells can differentiate into carcinoma associated [[Fibroblast|fibroblasts]], which furthers [[metastasis]].<ref name=":1" />
-The [[enhanced permeability and retention effect]] is the observation that the vasculature of tumors is often leaky and accumulates molecules in the blood stream to a greater extent than in normal tissue. This inflammation effect is not only seen in tumors, but in hypoxic areas of [[Myocardium|cardiac muscles]] following a [[myocardial infarction]].<ref>{{cite journal | vauthors = Palmer TN, Caride VJ, Caldecourt MA, Twickler J, Abdullah V | title = The mechanism of liposome accumulation in infarction | journal = Biochimica et Biophysica Acta - General Subjects | volume = 797 | issue = 3 | pages = 363–368 | date = March 1984 | pmid = 6365177 | doi = 10.1016/0304-4165(84)90258-7 }}</ref><ref name="Danhier">{{cite journal | vauthors = Danhier F, Feron O, Préat V | title = To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery | journal = Journal of Controlled Release | volume = 148 | issue = 2 | pages = 135–146 | date = December 2010 | pmid = 20797419 | doi = 10.1016/j.jconrel.2010.08.027 }}</ref> This permeable vasculature is thought to have several causes, including insufficient [[pericytes]] and a malformed [[basement membrane]].<ref name="Danhier" />
+=== Enhanced permeability and retention effect ===
+{{Main|Enhanced permeability and retention effect}}
+The enhanced permeability and retention effect is the observation that the vasculature of tumors tend to accumulate macromolecules in the blood stream to a greater extent than in normal tissue. This is due to the “leaky” nature of the vasculature around tumors, and a lacking [[lymphatic system]].<ref>{{Citation |last=Alasvand |first=Neda |title=Chapter 13 - Therapeutic Nanoparticles for Targeted Delivery of Anticancer Drugs |date=2017-01-01 |work=Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics |pages=245–259 |editor-last=Grumezescu |editor-first=Alexandru Mihai |url=https://www.sciencedirect.com/science/article/pii/B9780323527255000137 |access-date=2024-02-19 |publisher=Elsevier |doi=10.1016/b978-0-323-52725-5.00013-7 |isbn=978-0-323-52725-5 |last2=Urbanska |first2=Aleksandra M. |last3=Rahmati |first3=Maryam |last4=Saeidifar |first4=Maryam |last5=Gungor-Ozkerim |first5=P. Selcan |last6=Sefat |first6=Farshid |last7=Rajadas |first7=Jayakumar |last8=Mozafari |first8=Masoud}}</ref> The permeable vasculature allows for easier delivery of therapeutic drugs to the tumor, and the lacking lymphatic vessels contribute to an increased retention. The permeable vasculature is thought to have several causes, including insufficient [[pericytes]] and a malformed [[basement membrane]].<ref name="Danhier">{{cite journal |vauthors=Danhier F, Feron O, Préat V |date=December 2010 |title=To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery |journal=Journal of Controlled Release |volume=148 |issue=2 |pages=135–146 |doi=10.1016/j.jconrel.2010.08.027 |pmid=20797419}}</ref>
 === Hypoxia ===
-{{main|Tumor hypoxia}}
+{{Main|Tumor hypoxia}}
 [[File:Tumour stroma and extracellular matrix in hypoxia.svg|thumb|Tumor stroma and extracellular matrix in hypoxia]]
-The tumor microenvironment is often [[Hypoxia (medical)|hypoxic]]. As the tumor mass increases, the interior of the tumor becomes farther away from existing blood supply. While angiogenesis can reduce this effect, the [[partial pressure]] of oxygen is below 5&nbsp;mm [[Mercury (element)|Hg]] (venous blood has a partial pressure of oxygen at 40&nbsp;mm Hg) in more than 50% of locally advanced solid tumors.<ref name="Weber">{{cite journal | vauthors = Weber CE, Kuo PC | title = The tumor microenvironment | journal = Surgical Oncology | volume = 21 | issue = 3 | pages = 172–177 | date = September 2012 | pmid = 21963199 | doi = 10.1016/j.suronc.2011.09.001 }}</ref><ref name="dx">{{cite journal | vauthors = Blagosklonny MV | title = Antiangiogenic therapy and tumor progression | journal = Cancer Cell | volume = 5 | issue = 1 | pages = 13–17 | date = January 2004 | pmid = 14749122 | doi = 10.1016/S1535-6108(03)00336-2 | doi-access = free }}</ref> The hypoxic environment leads to [[Genome instability#Genome instability in cancer|genetic instability]], which is associated with cancer progression, via downregulating [[DNA repair]] mechanisms such as [[nucleotide excision repair]] and [[DNA mismatch repair|mismatch repair]] pathways.<ref>{{cite journal | vauthors = Bindra RS, Glazer PM | title = Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis | journal = Mutation Research | volume = 569 | issue = 1–2 | pages = 75–85 | date = January 2005 | pmid = 15603753 | doi = 10.1016/j.mrfmmm.2004.03.013 }}</ref> Hypoxia also causes the upregulation of [[HIF1A|hypoxia-inducible factor 1 alpha]], which induces angiogenesis and is associated with poorer prognosis and the activation of genes associated with metastasis,<ref name="dx" /> leading, for instance, to increased cell migration and also matrix remodeling.<ref name="physicalMicroenvironment"/>
+While angiogenesis can reduce the hypoxia in the tumor microenvironment, the [[partial pressure]] of oxygen is below 5 mmHg  in over 50% of locally advanced solid tumors, compared to venous blood which has a partial pressure of oxygen at 40-60 mmHg.<ref name=":2" /><ref name="Weber">{{cite journal |vauthors=Weber CE, Kuo PC |date=September 2012 |title=The tumor microenvironment |journal=Surgical Oncology |volume=21 |issue=3 |pages=172–177 |doi=10.1016/j.suronc.2011.09.001 |pmid=21963199}}</ref> A hypoxic environment leads to [[Genome instability#Genome instability in cancer|genetic instability]] by downregulating genes involved in [[DNA repair]] mechanisms such as [[nucleotide excision repair]] and [[DNA mismatch repair|mismatch repair]] pathways.<ref>{{Cite journal |last=Tang |first=Ming |last2=Bolderson |first2=Emma |last3=O’Byrne |first3=Kenneth J. |last4=Richard |first4=Derek J. |date=2021 |title=Tumor Hypoxia Drives Genomic Instability |url=https://www.frontiersin.org/articles/10.3389/fcell.2021.626229 |journal=Frontiers in Cell and Developmental Biology |volume=9 |doi=10.3389/fcell.2021.626229 |issn=2296-634X |pmc=PMC8007910 |pmid=33796526}}</ref> This genetic instability leads to a high number of mutated cells, and is associated with cancer progression.<ref name="Weber" /> Periods of mild and acute hypoxia and reoxygenation can lead cancer cells to adapt and grow into more aggressive phenotypes.<ref name=":2" />
+Hypoxia causes the upregulation of hypoxia induced factors (HIFs), which are transcription factors that decides how cells respond to a lack of oxygen.<ref name=":1" /> HIFs induces the transcription of thousands of genes, some of which induces angiogenesis or furthers metastasis, leading, for instance, to increased cell migration and matrix remodeling.<ref>{{Cite journal |last=Wicks |first=Elizabeth E. |last2=Semenza |first2=Gregg L. |date=2022-06-01 |title=Hypoxia-inducible factors: cancer progression and clinical translation |url=https://www.jci.org/articles/view/159839 |journal=The Journal of Clinical Investigation |language=en |volume=132 |issue=11 |doi=10.1172/JCI159839 |issn=0021-9738 |pmc=PMC9151701 |pmid=35642641}}</ref><ref name="physicalMicroenvironment" /> An increased HIF expression can lead tumor cells to shift their metabolism from aerobic to anaerobic, where they obtain energy through [[glycolysis]].<ref name=":3">{{Cite journal |last=Chen |first=Gaoqi |last2=Wu |first2=Kaiwen |last3=Li |first3=Hao |last4=Xia |first4=Demeng |last5=He |first5=Tianlin |date=2022 |title=Role of hypoxia in the tumor microenvironment and targeted therapy |url=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.961637 |journal=Frontiers in Oncology |volume=12 |doi=10.3389/fonc.2022.961637 |issn=2234-943X |pmc=PMC9545774 |pmid=36212414}}</ref> Cells with an elevated glucose metabolism produce [[lactic acid|lactate]], which decreases the pH in the microenvironment from a neutral and healthy 7.35-7.45 to an acidic 6.3-7.0. This phenomenon is described as the “[[Warburg effect (oncology)|Warburg effect]]”.<ref name=":3" /><ref>{{cite journal |vauthors=Lee SH, Griffiths JR |date=June 2020 |title=How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH |journal=Cancers |volume=12 |issue=6 |page=1616 |doi=10.3390/cancers12061616 |pmc=7352839 |pmid=32570870 |doi-access=free}}</ref> HIFs also regulate immune cells, and an increased expression can lead to the inactivation of anti-tumor functions. This furthers the survival of tumor cells and hinders anti-tumor treatment.<ref name=":3" />
-While a lack of oxygen can cause glycolytic behavior in cells, some tumor cells also undergo [[aerobic glycolysis]], in which they preferentially produce [[lactic acid|lactate]] from glucose even given abundant oxygen, called the [[Warburg effect (oncology)|Warburg effect]].<ref>{{cite journal | vauthors = Gatenby RA, Gillies RJ | title = Why do cancers have high aerobic glycolysis? | journal = Nature Reviews. Cancer | volume = 4 | issue = 11 | pages = 891–899 | date = November 2004 | pmid = 15516961 | doi = 10.1038/nrc1478 | s2cid = 10866959 }}</ref> No matter the cause, this leaves the extracellular microenvironment acidic (pH 6.5–6.9), while the cancer cells themselves are able to remain neutral (ph 7.2–7.4).<ref>{{cite journal | vauthors = Lee SH, Griffiths JR | title = How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH | journal = Cancers | volume = 12 | issue = 6 | page = 1616 | date = June 2020 | pmid = 32570870 | pmc = 7352839 | doi = 10.3390/cancers12061616 | doi-access = free }}</ref><ref>{{cite journal | vauthors = van Sluis R, Bhujwalla ZM, Raghunand N, Ballesteros P, Alvarez J, Cerdán S, Galons JP, Gillies RJ | display-authors = 6 | title = In vivo imaging of extracellular pH using 1H MRSI | journal = Magnetic Resonance in Medicine | volume = 41 | issue = 4 | pages = 743–750 | date = April 1999 | pmid = 10332850 | doi = 10.1002/(SICI)1522-2594(199904)41:4<743::AID-MRM13>3.0.CO;2-Z | doi-access =  | s2cid = 26815063 }}</ref><ref>{{cite journal | vauthors = Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ | display-authors = 6 | title = Acidity generated by the tumor microenvironment drives local invasion | journal = Cancer Research | volume = 73 | issue = 5 | pages = 1524–1535 | date = March 2013 | pmid = 23288510 | pmc = 3594450 | doi = 10.1158/0008-5472.CAN-12-2796 }}</ref>
 == Stromal cells ==
@@ Line 48: / Line 53: @@
 ==Immune cells==
 {{main|Cancer immunology}}
 [[File:Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models.svg|thumb|Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models]]
 [[File:Immune checkpoints of immunosuppressive actions associated with breast cancer.svg|thumb|Immune checkpoints of immunosuppressive actions associated with breast cancer]]