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=== Myeloid-derived suppressor cells and tumor associated macrophages ===
=== Myeloid-derived suppressor cells and tumor associated macrophages ===


Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells of [[Myeloid|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.<ref name="Bronte" /><ref>Alberto Mantovani, Paola Allavena, Antonio Sica & Frances Balkwill ''Cancer-related inflammation'' '''Nature''', Volume 454 24 July 2008 http://dx.doi.org/10.1038/nature07205</ref> Tumors can produce exosomes that stimulate inflammation via MDSCs.<ref name="Mathias" /><ref name="Valenti">Roberta Valenti, Veronica Huber, Manuela Iero, Paola Filipazzi, Giorgio Parmiani, & Licia Rivoltini ''Tumor-released microvesicles as vehicles of immunosuppression'' '''Cancer Research''', Volume 67, 1 April 2007, Pages 2912-1915 http://dx.doi.org/10.1158/0008-5472.CAN-07-0520</ref> This group of cells include some [[Macrophage#Cancer|tumor associated macrophages]] (TAMs).<ref name="Bronte">http://www.nature.com/nri/posters/mdscs/nri1005_mdscs_poster.pdf Vincenzo Bronte and Dmitry Gabrilovich ''Myeloid-derived suppressor cells'' '''Nature'''</ref> TAMs are a central component in the strong link between [[Inflammation#Cancer|chronic inflammation and cancer]]. TAMs are recruited to the tumor as a response to cancer-associated inflammation.<ref>Frances Balkwill, Kellie A. Charles, & Alberto Mantovani ''Smoldering and polarized inflammation in the initiation and promotion of malignant disease'' '''Cancer Cell''', Volume 7, Issue 3, March 2005, Pages 211–217 http://dx.doi.org/10.1016/j.ccr.2005.02.013</ref> Unlike normal macrophages, TAMs lack cytotoxic activity.<ref>Bin-Zhi Qian, Jeffrey W. Pollard ''Macrophage Diversity Enhances Tumor Progression and Metastasis'' '''Cell''', Volume 141, Issue 1, 2 April 2010, Pages 39–51 http://dx.doi.org/10.1016/j.cell.2010.03.014</ref> TAMs have been induced ''in vitro'' by exposing macrophage progenitors to different immune regulatory cytokines, such as [[interleukin 4]] (IL-4) and [[interleukin 13]] (IL-13).<ref name="Hanahan" /> TAMs gather in necrotic regions of tumors where they are associated with hiding cancer cells from normal immune cells by secreting [[interleukin 10]] (IL-10),<ref name ="Solinas" /> aiding angiogenesis by secreting [[vascular endothelial growth factor]] (VEGF) and [[nitric oxide synthase]](NOS),<ref name ="Weber" /> supporting tumor growth by secreting [[epidermal growth factor]] (EGF)<ref name="Solinas" /> and remodeling the [[Extracellular matrix|ECM]].<ref name="Weber" /> TAMs show sluggish [[NF-κB]] activation, which allows for the smoldering inflammation seen in cancer.<ref>Subhra K. Biswas, Lisa Gangi, Saki Paul, Tiziana Schioppa, Alessandra Saccani, Marina Sironi, Barbara Bottazzi, Andrea Doni, Bronte Vincenzo, Fabio Pasqualini, Luca Vago, Manuela Nebuloni, Alberto Mantovani, and Antonio Sica ''A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation)'' '''Blood''', Volume 107, Issue 5, 3 November 2005, Pages 2112-2122 http://dx.doi.org/10.1182/blood-2005-01-0428</ref> An increased amount of TAMs is associated with worse prognosis.<ref>Wei Zhang, Liang Wang, Daobin Zhou, Quancai Cui, Dachun Zhao, & Yongji Wu ''Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified'' '''Leukemia & Lymphoma''', Volume 52, Issue 1, January 2011, Pages 46-52 http://dx.doi.org/10.3109/10428194.2010.529204</ref><ref>Bi Cheng Zhang, Juan Gao, Jun Wang, Zhi Guo Rao, Bao Cheng Wang, & Jian Fei Gao ''Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma'' '''Medical Oncology''', Volume 28, Issue 4 December 2011, Pages 1447-1452 http://dx.doi.org/10.1007/s12032-010-9638-5</ref> TAMs represent a potential target for novel cancer therapies.
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells of [[Myeloid|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.<ref name="Bronte" /><ref>{{cite journal|first1= Alberto |last1=Mantovani |first2=Paola |last2=Allavena|first3=Antonio |last3=Sica |first4= Frances |last4=Balkwill |title = Cancer-related inflammation |journal= Nature|volume = 454 24 July 2008 |url = http://dx.doi.org/10.1038/nature07205 |doi=10.1038/nature07205}}</ref> Tumors can produce exosomes that stimulate inflammation via MDSCs.<ref name="Mathias" /><ref name="Valenti">{{cite journal|first1=Roberta |last1=Valenti|first1=Veronica |last2=Huber|first3=Manuela |last3=Iero|first4=Paola |last4=Filipazzi|first5=Giorgio |last5=Parmiani|first6= Licia |last6=Rivoltini |title = Tumor-released microvesicles as vehicles of immunosuppression |journal= Cancer Research|volume = 67 |date= 1 April 2007 |pp= 2912-1915 |url = http://dx.doi.org/10.1158/0008-5472.CAN-07-0520 |doi=10.1158/0008-5472.CAN-07-0520}}</ref> This group of cells include some [[Macrophage#Cancer|tumor associated macrophages]] (TAMs).<ref name="Bronte">{{cite journal|url=http://www.nature.com/nri/posters/mdscs/nri1005_mdscs_poster.pdf |first1=Vincenzo |last1=Bronte |first2=Dmitry |last2=Gabrilovich |title= Myeloid-derived suppressor cells (Poster) |journal= Nature}}</ref> TAMs are a central component in the strong link between [[Inflammation#Cancer|chronic inflammation and cancer]]. TAMs are recruited to the tumor as a response to cancer-associated inflammation.<ref>{{cite journal|first1=Frances Balkwill|first1=Kellie A. |last1=Charles|first1= Alberto |last2=Mantovani |title = Smoldering and polarized inflammation in the initiation and promotion of malignant disease |journal= Cancer Cell|volume = 7 |issue= 3, March 2005 |pp= 211–217 |url = http://dx.doi.org/10.1016/j.ccr.2005.02.013 |doi=10.1016/j.ccr.2005.02.013 }}</ref> Unlike normal macrophages, TAMs lack cytotoxic activity.<ref>{{cite journal|first1=Bin-Zhi |last1=Qian|first2=Jeffrey W. |last2=Pollard |title = Macrophage Diversity Enhances Tumor Progression and Metastasis |journal= Cell|volume = 141 |issue= 1 |date= 2 April 2010 |pp= 39–51 |url = http://dx.doi.org/10.1016/j.cell.2010.03.014 |doi=10.1016/j.cell.2010.03.014}}</ref> TAMs have been induced |title = in vitro by exposing macrophage progenitors to different immune regulatory cytokines, such as [[interleukin 4]] (IL-4) and [[interleukin 13]] (IL-13).<ref name="Hanahan" /> TAMs gather in necrotic regions of tumors where they are associated with hiding cancer cells from normal immune cells by secreting [[interleukin 10]] (IL-10), aiding angiogenesis by secreting [[vascular endothelial growth factor]] (VEGF) and [[nitric oxide synthase]](NOS),<ref name ="Weber" /> supporting tumor growth by secreting [[epidermal growth factor]] (EGF)<ref name="Solinas" /> and remodeling the [[Extracellular matrix|ECM]].<ref name="Weber" /> TAMs show sluggish [[NF-κB]] activation, which allows for the smoldering inflammation seen in cancer.<ref>{{cite journal|first1=Subhra K. Biswas |first=Lisa Gangi |first=Saki Paul |first1=Tiziana |last1=Schioppa |first2=Alessandra |last2=Saccani |first3=Marina |last3=Sironi |first4=Barbara |last4=Bottazzi |first5=Andrea|last5= Doni |first6=Bronte |last6=Vincenzo |first7=Fabio |last7=Pasqualini |first8=Luca |last8=Vago |first9=Manuela |last9=Nebuloni |first10=Alberto |last10=Mantovani |first11=Antonio |last11=Sica |title = A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation) |journal= Blood|volume = 107 |issue= 5 |date=3 November 2005 |pp= 2112-2122 |url = http://dx.doi.org/10.1182/blood-2005-01-0428 |doi=10.1182/blood-2005-01-0428}}</ref> An increased amount of TAMs is associated with worse prognosis.<ref>{{cite journal|first1=Wei |last1=Zhang |first2=Liang |last2=Wang |first3=Daobin |last3=Zhou |first4=Quancai |last4=Cui |first5=Dachun |last5=Zhao |first6= Yongji |last6=Wu |title = Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified |journal= Leukemia |last= Lymphoma|volume = 52 |issue= 1 |date= January 2011 |pp= 46-52 |url = http://dx.doi.org/10.3109/10428194.2010.529204 |doi=10.3109/10428194.2010.529204}}</ref><ref>{{cite journal|first1=Bi Cheng |last1=Zhang |first2=Juan |last2=Gao |first3=Jun |last3=Wang |first5=Zhi Guo |last=5Rao |first6=Bao |last6=Cheng Wang, |first7= Jian Fei |last7=Gao |title = Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma |journal= Medical Oncology|volume = 28 |issue= 4 |date=December 2011 |pp= 1447-1452 |url = http://dx.doi.org/10.1007/s12032-010-9638-5 |doi=/10.1007/s12032-010-9638-5}}</ref> TAMs represent a potential target for novel cancer therapies.


TAMs are associated with using [[Exosome (vesicle)|exosomes]] (vesicles used by mammalian cells to secrete intracellular contents) to deliver invasion-potentiating [[microRNA]] (miRNA) into cancerous cells, specifically breast cancer cells.<ref name="Mathias">Rommel A. Mathias, Shashi K. Gopal, Richard J. Simpson ''Contribution of cells undergoing epithelial–mesenchymal transition to the tumour microenvironment'' '''Journal of Proteomics''', Volume 78, 14 January 2013, Pages 545–557 http://dx.doi.org/10.1016/j.jprot.2012.10.016</ref><ref>Mei Yang, Jingqi Chen, Fang Su, Bin Yu, Fengxi Su, Ling Lin, Yujie Liu, Jian-Dong Huan, & Erwei Song ''Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells'' '''Molecular Cancer''' Volume 10, Issue 117, 22 September 2011, http://dx.doi.org/10.1186/1476-4598-10-117</ref>
TAMs are associated with using [[Exosome (vesicle)|exosomes]] (vesicles used by mammalian cells to secrete intracellular contents) to deliver invasion-potentiating [[microRNA]] (miRNA) into cancerous cells, specifically breast cancer cells.<ref name="Mathias">{{cite journal|first1=Rommel A. |last1=Mathias |first2=Shashi K. |last2=Gopal |first3=Richard J. |last3=Simpson |title = Contribution of cells undergoing epithelial–mesenchymal transition to the tumour microenvironment |journal= Journal of Proteomics|volume = 78 |date=14 January 2013 |pp= 545–557 |url = http://dx.doi.org/10.1016/j.jprot.2012.10.016 |doi=10.1016/j.jprot.2012.10.016}}</ref><ref>{{cite journal|first1=Mei |last1=Yang |first2=Jingqi |last2=Chen |first3=Fang |last3=Su |first4=Bin |last4=Yu |first5=Fengxi |last5=Su |first6=Ling |last6=Lin |first7=Yujie |last7=Liu |first8=Jian-Dong |last8=Huan |first9= Erwei |last9=Song |title = Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells |journal= Molecular Cancer |volume= 10 |issue= 117 |date=22 September 2011 |url = http://dx.doi.org/10.1186/1476-4598-10-117 |doi=10.1186/1476-4598-10-117}}</ref>


=== Tumor infiltrating lymphocytes ===
=== Tumor infiltrating lymphocytes ===

Revision as of 02:21, 25 June 2015

The tumor microenvironment is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules and the extracellular matrix (ECM).[1] The tumor and the surrounding microenvironment are closely related and interact constantly. 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, such as in immuno-editing.

The tumor microenvironment contributes to tumour heterogeneity.

History

The interplay between the tumor and its microenvironment was part of Stephen Paget's "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.[2]

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.[3][4]

Vasculature

80–90% of cancer are carcinomas, or cancers that form in the epithelial tissue.[5] This tissue is not vascularized, which prevents tumors from growing greater than 2mm in diameter without inducing new blood vessels.[6] The process of angiogenesis is dysregulated to feed the cancer cells and as a result the vasculature formed differs from that of normal tissue.

Enhanced permeability and retention effect

The enhanced permeability and retention effect (EPR 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 cardiac muscles following a myocardial infarction (MI or heart attack).[7][8] This leaky vasculature is thought to have several causes, including insufficient pericytes and a malformed basement membrane.[8]

Hypoxia

The tumor microenvironment is often hypoxic. As the tumor mass increases, the interior of the tumor grows farther away from existing blood supply. While angiogenesis can reduce this affect, the partial pressure of oxygen is below 5 mm Hg (venous blood has a partial pressure of oxygen at 40 mm Hg) in more than 50% of locally advanced solid tumors.[9][10] The hypoxic environment leads to genetic instability, which is associated with cancer progression, via downregulating DNA repair mechanisms such as nucleotide excision repair (NER) and mismatch repair (MMR) pathways.[11] Hypoxia also causes the upregulation of hypoxia-inducible factor 1 alpha (HIF1-α), which induces angiogenesis and is associated with poorer prognosis and the activation of genes associated with metastasis.[10]

While a lack of oxygen can cause glycolytic behavior in cells, tumor cells also undergo aerobic glycolysis, in which they preferentially produce lactate from glucose even given abundant oxygen, called the Warburg effect.[12] 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). It has been shown that this induces greater cell migration in vivo and in vitro, possibly by promoting degradation of the ECM.[13][14]

Reactive stromal cells

The stroma of a carcinoma is the connective tissue below the basal lamina. This includes fibroblasts, ECM, immune cells and other cells and molecules. The stroma surrounding a tumor often reacts to intrusion via inflammation, similar to how it might respond to a wound.[15] Inflammation can encourage angiogenesis, speed the cell cycle and prevent cell death, all of which augments tumor growth.[16]

Carcinoma associated fibroblasts

Carcinoma associated fibroblasts (CAFs) are a heterogenous group of fibroblasts whose function is pirated by cancer cells and redirected toward carcinogenesis[17] 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 (MSCs, often derived from bone marrow), or via epithelial-mesenchymal transition (EMT) or endothelial-mesenchymal transition (EndMT).[18][19][20] Unlike their normal ounterparts, CAFs do not retard cancer growth in vitro.[21] CAFs perform several functions that support tumor growth, such as secreting vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), and other pro-angiogenic signals to induce angiogenesis.[9] CAFs can also secrete transforming growth factor beta (TGF-β), which is associated with EMT, a process by which cancer cells can metastasize,[22] and is associated with inhibiting cytotoxic T cells and natural killer T cells.[23] As fibroblasts, CAFs are able to rework the ECM to include more paracrine survival signals such as IGF-1 and IGF-2, thus promoting survival of the surrounding cancer cells. CAFs are also associated with the Reverse Warburg Effect where the CAFs perform aerobic glycolysis and feed lactate to the cancer cells.[17]

Several markers identify CAFs, including expression of α smooth muscle actin (αSMA), vimentin, platelet-derived growth factor receptor α (PDGFR-α), platelet-derived growth factor receptor β (PDGFR-β), fibroblast specific protein 1 (FSP-1), and fibroblast activation protein (FAP).[19] None of these factors can be used to differentiate CAFs from all other cells by itself.

Myeloid-derived suppressor cells and tumor associated macrophages

Myeloid-derived suppressor cells (MDSCs) are a heterogenous 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.[24][25] Tumors can produce exosomes that stimulate inflammation via MDSCs.[26][27] This group of cells include some tumor associated macrophages (TAMs).[24] TAMs are a central component in the strong link between chronic inflammation and cancer. TAMs are recruited to the tumor as a response to cancer-associated inflammation.[28] Unlike normal macrophages, TAMs lack cytotoxic activity.[29] TAMs have been induced |title = in vitro by exposing macrophage progenitors to different immune regulatory cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13).[17] TAMs gather in necrotic regions of tumors where they are associated with hiding cancer cells from normal immune cells by secreting interleukin 10 (IL-10), aiding angiogenesis by secreting vascular endothelial growth factor (VEGF) and nitric oxide synthase(NOS),[9] supporting tumor growth by secreting epidermal growth factor (EGF)[30] and remodeling the ECM.[9] TAMs show sluggish NF-κB activation, which allows for the smoldering inflammation seen in cancer.[31] An increased amount of TAMs is associated with worse prognosis.[32][33] TAMs represent a potential target for novel cancer therapies.

TAMs are associated with using exosomes (vesicles used by mammalian cells to secrete intracellular contents) to deliver invasion-potentiating microRNA (miRNA) into cancerous cells, specifically breast cancer cells.[26][34]

Tumor infiltrating lymphocytes

Tumor infiltrating lymphocytes (TILs) are lymphocytes that penetrate a tumor. TILs have a common origin with myelogenous cells at the hematopoietic stem cell, but diverge in development. Concentration is generally positively correlated.[30] However, only in melanoma has autologous TIL transplant succeeded as a treatment.[35] 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 (NK cells).[27][36] This suggests that cancer cells actively work to restrain TILs.

Extracellular matrix remodeling

Fibroblasts are in charge of laying down most of the collagens, elastin, glycosaminoglycans, proteoglycans (e.g. perlecan), and glycoproteins in the ECM. As many fibroblasts are transformed into CAFs during carcinogenesis, this reduces the amount of ECM produced and the ECM that is produced can be malformed, like collagen being loosely woven and non-planar, possibly even curved.[37] In addition, CAFs produce matrix matrix metalloproteinases (MMP) that cleave the proteins within the ECM.[9] CAFs are also able to disrupt the ECM via force, generating a track that a carcinoma cell can follow.[38] In either case, destruction of the ECM 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 ECM also modulates the signaling cascades controlled by the interaction of cell-surface receptors and the ECM, and it also reveals binding sites previously hidden, like the integrin alpha-v beta-3 (αVβ3) on the surface of melanoma cells can be ligated to rescue the cells from apoptosis after degradation of collagen.[39][40] In addition, the degradation products may have downstream effects as well that can increase cancer cell tumorigenicity and can serve as potential biomarkers.[39] ECM destruction also releases the cytokines and growth factors stored therein (for example, VEGF, basic fibroblast growth factor (bFGF), insulin-like growth factors (IGF1 and IGF2), TGF-β, EGF, heparin-binding EGF-like growth factor (HB-EGF), and tumor necrosis factor (TNF), which can increase the growth of the tumor.[37][41] Cleavage of ECM 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.[37]

ECM stiffening is associated with tumor progression.[42] This stiffening may be partially attributed to CAFs secreting lysyl oxidase (LOX), an enzyme that cross-links the collagen IV found in the ECM.[19][43]

Clinical implications

Drug development

Numerous high throughput screens for cancer therapeutics are performed in vitro on cancer cell lines without the accompanying microenvironment, but current studies are also investigating the effects of supportive stroma cells and their resistance to therapy. These studies revealed interesting therapeutic targets in the microenvironment includint integrins or chemokines.[44] These were missed by initial screens for anti-cancer drugs and might also help explain why so few initially identified drugs are highly potent in vivo.

Nanocarrier vehicles (~20–200 nm in diameter) have been developed for transport of drugs and other therapeutic molecules, so that these therapies can be targeted to selectively extravasate through tumor vasculature via the EPR effect. Using a nanocarrier is now considered the gold standard of targeted cancer therapy because it targets tumors that few that are hypovascularized, like prostate and pancreatic tumors.[8][45] These efforts include protein capsids[46] and liposomes.[47] However, as some important, normal tissues, such as the liver and kidneys, also have fenestrated endothelium, great care must be taken to use the correct size (10–100 nm, with greater retention in tumors seen in using larger nanocarriers) and charge (anionic or neutral).[8] Lymphatic vessels do not usually develop with the tumor, leading to increased interstitial fluid pressure, which made abrogate the journey of these nanocarriers to the tumor.[8][48]

Current Therapies

Bevacizumab is clinically approved to treat a variety of cancer by targeting VEGF-A, which is produced by both CAFs and TAMs, thus slowing angiogenesis. Many other small molecule inhibitors exist that block the receptors for the growth factors released, thus making the cancer cell deaf to much of the paracrine signaling produced by CAFs and TAMs. These inhibitors include Sunitinib, Pazopanib, Sorafenib and Axitinib, all of which inhibit platelet derived growth factor receptors (PDGF-Rs) and VEGF receptors (VEGFRs). Cannabidiol, a cannabis derivate without psychoactive side effects, has also been shown to inhibit the expression of VEGF in Kaposi's sarcoma cells.[49]

Natalizumab is a monoclonal antibody that was designed to target one of the molecules responsible for cell adhesion (integrin VLA-4) and has promising in vitro activity in B cell lymphomas and leukemias.[44]

Trabectedin is known to have immunomodulatory effects that inhibit TAMs.[30]

Current liposome formulations that encapsulate anti-cancer drugs for selective uptake to tumors via the EPR effect include: Doxil and Myocet, both of which encapsulate doxorubicin (a DNA intercalator and common chemotherapeutic); DaunoXome, which encapsulates daunorubicin (another DNA intercalator similar to doxorubicin); and Onco-TCS, which encapsulates vincristine (a molecule which constitutively induces formation of microtubules, dysregulating cell division). Another novel utilization of the EPR effect comes from Protein-bound paclitaxel (marketed under the trade name Abraxane) where paclitaxel (a molecule which dysregulates cell division via stabilization of microtubules) is bound to albumin to add bulk and aid delivery.

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