Collagen VI: A New Candidate Breast Cancer Marker Linked to Resistance to Platinum-Based Cancer Drugs.

摘要

We have observed a dramatic increase of adipocyte-derived matrix protein collagen VI (COL6) level during cancer progression, particularly it relates to a discrete C-terminal domain of the alpha3 subunit of COL6. I have established 2 lines of transgenic mice which overproduce C- terminal domain, called 'C5', of the COL6A3 (COL6A3-C5) under the control of MMTV promoter and crossed with MMTV-PyMT mice to see the C5 effects on mammary tumor progression in vivo. Our results indicate that COL6A3-C5 augments primary tumor growth and pulmonary metastasis in MMTV-PyMT mammary tumor mice model in vivo. Based on the cDNA microarray data with tumor tissues, COL6A3-C5 seems to be a signaling molecule regulating a kinase (or a phosphatase) activity which may be through a specific receptors that remains to be identified. Furthermore, treatment with COL6A3-C5 neutralizing antibodies in MMTV-PyMT mice protects mammary tumor progression. I have determined the effects of COL6 on the TZD mediated enhancement of cisplatin susceptibility with PyMT/COL6-/- mice. Tumor growth in PyMT/COL6-/- mice was significantly attenuated either by cisplatin or by a combination of cisplatin and TZD compared to PyMT/COL6+/+. To better understand the COL6 effects on drug resistance, I have tested COL6A3-C5 neutralizing antibodies in combination with cisplatin and TZD using the primary cultured tumor cells implantation system. To visualize the tumor progression in vivo, I generated MMTV-F635 transgenic mice which overproduce an infrared fluorescence protein specifically in the mammary epithelial cells. This allows me for the first time to monitor efficacy of treatment modalities longitudinally in mice.