CXCR4 receptor supplants Id1 gene as major player in tumor angiogenesis

New research contradicts the theory that Id gene products control angiogenesis and vascularization in tumors. Instead, scientists report in the October issue of Cancer Cell, the chemokine receptor CXCR4 may play this important role by attracting endothelial cells to the site of cell transformation.

In previous research, Id1-knockout mice resisted the growth of transplanted tumor cells by inhibiting tumor angiogenesis, senior investigator Dr. Rhoda M. Alani told Reuters Health. But because clinical trials of agents targeting Id have proved disappointing, her team examined the role of Id1 in what they consider to be a more genetically relevant tumor model system involving cutaneous neoplasms induced by topical carcinogens.Contrary to findings from xenograft models, Dr. Alani, at the Johns Hopkins University School of Medicine in Baltimore, and her colleagues report, skin cancers developed more frequently and grew larger in the knockout animals compared with wild-type mice. However, blood vessel density and caliber were not affected by Id1 inactivation.Further investigation revealed a 50% reduction in skin-specific gamma-delta T cells, which participate in tumor immunosurveillance. The authors traced this decrease to defective homing of the cells to the skin because CXCR4 expression in the Id1-/- T cells was less than 10% that found in Id1+/+ cells.Dr. Alani pointed out that other investigators have documented a similar association between reduced CXCR4 expression and breast and kidney cell transformation.”So we think that the CXCR4 receptor may be important for cancer invasiveness and progression, and we also think it may be important for endothelial cells involved in tumor angiogenesis.”In contrast, she posits that growth of tumor xenografts in Id1+/+ animals is analogous to metastasis, and agents that target Id1 are disrupting the metastatic process.Her group’s findings may actually advance cancer research more rapidly than Id-related findings. T-cell CXCR4 is also an HIV co-receptor, Dr. Alani explained, and an investigational CXCR4 antagonist is already in clinical trials testing its efficacy as an HIV treatment.As a result of her group’s research, the company evaluating the CXCR4 antagonist “is interested in testing the agent in cancer to see if the receptor is important for tumor invasiveness and for angiogenesis.”(Source: Cancer Cell 2003;4:291-299: Reuters Health: Karla Gale: October 24, 2003: Oncolink)