2. Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9, Canada.
3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
4. Pfizer, Oncology Research Unit, 10724 Science Center Drive, 92121San Diego, CA, USA.
5. Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
6. Department of Radiation Oncology University Health Network, 610 University Ave, Toronto, ON M5G 1L7, Canada.
7. Department of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9, Canada.
8. Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9, Canada.
Tumor-stroma interactions are regulated through a network of autocrine and paracrine signaling pathways that are crucial for many aspects of tumor development. Activation and signaling through the HGF/Met pathway have been shown to increase cell motility and reduce sensitivity to chemotherapy. We used a patient-derived colon-cancer epithelial stem cell line and patient-derived normal fibroblasts (NFs) or cancer-associated fibroblasts (CAFs), chosen for high HGF expression, to investigate the contribution of stromal signaling through the MET pathway in tumor growth and sensitivity to the Met inhibitor crizotinib. Co-injection of the colon cancer cell line with NFs or CAFs resulted in significantly increased tumor take. Additionally, tumors derived from the co-injections showed increased growth rates, an invasion of host stroma, increased expression of vimentin, and reduced sensitivity to crizotinib. These data demonstrate that stromal signaling through HGF/Met from adjacent fibroblasts leads to a more aggressive tumor phenotype, and can cause resistance to treatments targeting this pathway.
Keywords: EMT, crizotinib, colorectal cancer, cancer-associated fibroblasts