ABCB5

Clinical significance

ABCB5 has been suggested to regulate skin progenitor cell fusion and mediate chemotherapeutic drug resistance in stem-like tumor cell subpopulations in human melanoma, colorectal cancer, and malignant pleural mesothelioma. 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.

In colorectal cancer, ABCB5 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. It has been shown that in some highly aggressive tumors, such as mesothelioma and melanoma, ABCB5 contributes 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 cancer stem cells and tumor bulk population (in a rheostat manner termed "cancer stem cell rheostasis"). ABCB5 was shown to maintain the slow-cycling melanoma stem cells using this cytokine signaling loop, which became more differentiated upon ABCB5 interference (e.g. 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 is 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.

References

References

1. (October 1996). "Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database". Human Molecular Genetics.
2. (November 2003). "Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter". The Journal of Biological Chemistry.
3. (April 2005). "Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes". Pigment Cell Research.
4. (May 2005). "ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma". Cancer Research.
5. (December 2009). "Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma". Pigment Cell & Melanoma Research.
6. (January 2008). "Identification of cells initiating human melanomas". Nature.
7. (November 2010). "Isolation of tumorigenic circulating melanoma cells". Biochemical and Biophysical Research Communications.
8. (February 2011). "VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth". Cancer Research.
9. (August 2011). "ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients". Cancer Research.
10. Milosevic, V. et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.Int. J. Cancer, https://doi.org/10.1002/ijc.32419
11. (August 2014). "ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit". Cancer Research.
12. (July 2014). "ABCB5 is a limbal stem cell gene required for corneal development and repair". Nature.