ABCB5 has been suggested to regulate skin progenitor cell fusion and mediate chemotherapeutic drug resistance in stem-like tumor cell subpopulations in human malignant melanoma. It is commonly over-expressed on circulating melanoma tumour cells. Furthermore, the ABCB5+ melanoma- initiating cells were demonstrated to express FLT1 (VEGFR1) receptor tyrosine kinase which was functionally required for efficient xenograft tumor formation, as demonstrated by shRNA knockdown experiments.
More recently, the ABCB5 molecule has been shown to be functionally relevant to carcinogenesis, demonstrated in colorectal cancer where it was shown to act as a mediator of 5-FU patient chemoresistance, and had a further direct role in tumorigenesis shown by shRNA-mediated colorectal cancer cell-line ABCB5 knockdowns that impeded tumorigenesis in human-to-mouse xenografts. These data revealed multiple roles for ABCB5 in cancer progression and chemoresistance, making it an attractive target for combined therapy. ABCB5 was similarly demonstrated in melanoma to be functionally important to multi-drug chemotherapy resistance, and tumor growth, controlling a proinflammatory signaling circuit utilizing TLR4, IL-1β, IL8 and CXCR1 signaling involving reciprocal paracrine interactions between the melanoma stem cell and tumor bulk population (in a rheostat manner termed "cancer stem cell rheostasis" by the authors). ABCB5 was shown to maintain the slow-cycling melanoma stem cells using this cytokine signaling loop, which became more differentiated upon ABCB5 interference (eg WFDC1 melanocyte differentiation marker increased, cancer cells were faster growing in vitro, tumors were more pigmented), or CXCR1 blockade (slow-cycling ABCB5+ cells entered the cell-cycle).
In normal physiology ABCB5 was shown to be a functional marker for adult limbal stem cells of the cornea; ABCB5+ cells could regrow a human cornea on a mouse with limbal stem cell deficiency (LSCD - a blindness disease of the corneal limbus) while ABCB5- cells could not, indicating a therapeutic potential for treating some types of blindness. ABCB5 was further shown to be anti-apoptotic in these adult stem cells.
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