Interaction of Cancer Stem-Like Cells and Growth Factor Receptors in the Evolution of Colorectal Cancers during Aging
Seema Sethi, Edi Levi, Adhip Majumdar. Wayne State University Medical School, Detroit, MI; VA Hospital, Detroit, MI
Background: The incidence of colorectal carcinoma increases exponentially with age. The exact reason for this is yet unknown. We have previously reported that the age related rise in adenomatous polyps in normal appearing mucosa of humans is associated with increased expression of cancer stem cell (CSC) markers. Additionally we have demonstrated that this is accompanied by an increased expression of growth factor receptors such as epidermal growth factor receptor (EGFR) and insulin like growth factor receptor (IGFR), suggesting a relationship between the CSCs and EGFR. We hypothesize that Growth factor receptor over-expression may be involved in the upregulation of CSCs during development of colon cancer.
Design: We investigated the co-expression of phosphorylated EGFR and phoshorylated IGFR in the same cells as the stem cell marker CD166 in 4 study groups: (1) colonic adenocarcinomas in patients <60 years; (2) colonic adenocarcinomas in patients >60 years; (3) adenomatous polyps and (4) normal colonic mucosa of patients with polyps (<60 vs >60). We used double color immunofluorescence staining pairing a growth factor receptor marker with CD166. The co-expression score was determined by counting the percentage of co-expressing cells within a crypt and counting 20 crypts and averaging per crypt. Data was statistically analyzed using Chi-Square tests.
Results: We found a significant increase in co-expression of pEGFR/CD166 and pIGFR/CD166 in normal mucosa of aging individuals, when stratified by 60 years of age (p=0.01 for pIGFR/CD166, p=0.001 for pEGFR; <60 vs. >60 years of age). We also investigated the co-expression of pIGFR/CD166 and pEGFR/CD166 in colon adenomas (n=20). In all adenomas the level of co-expression was higher than both groups of normal colonic mucosa samples. In addition the co-expression of pEGFR and pIGFR with CD166 was higher in colonic adenocarcinomas of >60 compared to <60. (p=0.001 for both pEGFR and pIGFR).
Conclusions: These findings suggest that cancer stem cells show increased expression of growth factor receptors during cancer development and aging. This will give a survival and proliferative advantage and allow for accumulation of new mutations to promote the cancer phenotype. The mechanism for the interaction between the two systems is unknown but microRNAs are the most likely culprits.
Tuesday, March 20, 2012 8:45 AM
Platform Session: Section D, Tuesday Morning