Altered or over-expression of growth factors or their receptors is thought to significantly contribute to tumorigenesis. The erbB kinases, especially the proto-oncogene erbB2, and major ligands (EGF and neuregulin groups) are implicated in epithelial malignancies such as breast and colon. EGFR and TGFalpha co- expression in colon cancer is associated with neoplastic progression through growth factor independence. Immunohistochemical studies of the erbB kinase family in colon adenomas with concurrent invasive cancer demonstrate increased expression of erbB2 in the neoplastic cell population. In addition, I present the new finding of co-expressed heregulin (cognate ligand for human erB3 and 4) and erbB2 in these polyps and cancers as well as in colon adenoma and carcinoma cell lines. I demonstrate a significant biologic response to heregulin, not previously described in colon cell lines, and loss of cell growth by blockade of the erB2 receptor, emphasizing the importance of activated erbB2 as a mechanism for cell growth in the colon. As both EGFR and erbB3 will signal through erbB2 as heterodimers, I propose that activation of erbB2 is central to the control of down stream signaling and that activated erbB2 receptor is pivotal in the progression of colon cancer. To study the role of erbB2 and related kinases and ligands in colon carcinogenesis, four colon cell lines have been characterized for the role of erbB signaling: a benign adenoma line, two growth factor dependent (GFD) carcinoma lines, and a growth factor independent (GFI) carcinoma cell line. They were selected to represent stages in the multi-step progression of colon carcinogenesis. Blockade of EGFR and erbB2 receptor activation in these cell lines is associated with dramatic biologic response further supporting a role for functional erbB2 on colon carcinogenesis. Employing these unique cell lines, representative of colon cancer progression that exhibit autocrine activation by TGFalpha and heregulin, I propose to study erbB2 signaling in colon carcinogenesis. The objective is to define the role of the erbB2 activation through TGFalpha and heregulin in this in vitro model of tumor progression, specifically to determine: 1) the functional expression profile of the erbB kinases and these ligands in the model cell lines and characterize tissue expression of the same to support the biologic relevance of erbB kinases in carcinogenesis, 2) the signal pathways and biologic response mediated by erbB2 activation, and 3) the effects of erbB signal-based modulation through erbB2, PI3K, and MED/MAPK pathways that contributes to neoplastic progression as characterized by cell growth and resistance to apoptosis.
| Venkateswarlu, Srinivas; Dawson, Dawn M; St Clair, Patricia et al. (2002) Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells. Oncogene 21:78-86 |
