Integrin Signaling during Tumor Invasion and Angiogenesis

Dominant mutations in oncogenes and recessive mutations in tumour suppressor genes disrupt the regulatory circuits that govern cell fate, endowing neoplastic cells with the ability to survive and proliferate even if appropriate extracellular cues are not available. As a consequence, cells that have undergone neoplastic transformation are much less dependent on matrix adhesion for their survival and proliferation. In spite of their relative anchorage independence, cancer cells still benefit from integrin signals, both during tumor initiation and tumour progression. Specific integrin signals enable cancer cells to detach from neighboring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments.

α6β4 in blood vessels (left) and at the invasive edges (right) of human papillary thyroid cancer.

We are using mouse molecular genetics to examine the role of α6β4 signaling in tumor progression. Wenjun Guo has introduced a targeted deletion of the β4 signaling domain in MMTV-Neu mice, which develop mammary tumors. His results have indicated that  α6β4 signaling promotes tumor cell proliferation, thereby facilitating tumor initiation and growth, and that it cooperates with ErbB2 signaling to disrupt cell polarity, thus promoting tumor invasion. Similar studies by Toshiaki Yoshioka have revealed a key role of α6β4 signaling in prostate tumor progression in TRAMP mice. We are currently studying the mechanisms by which α6β4 signaling coordinately disrupts epithelial polarity and promotes invasive growth. To study the role of FAK signaling in tumor progression, we are crossing FAK-conditional null mice to mouse models of cancer.

α6β4-RTK signaling in normal cells and in cancer cells.

Sotiris Nikolopoulos has examined tumor angiogenesis in β4 mutant mice. His results have provided genetic evidence that α6β4 signaling controls pathological angiogenesis by promoting the acquisition of an invasive phenotype by angiogenic endothelial cells. The discovery that α6β4 signaling plays a similar role in cancer cell invasion and in tumor angiogenesis suggests that its inhibition may be especially beneficial for cancer therapy.