Colorectal cancers aberrantly express gastrin-releasing peptide (GRP) hormone and its cognate receptor (GRPR). Ample in vivo and in vitro experiments suggest that GRP, or bombesin (BN), the pharmacological homologue of GRP, promotes colorectal cancer growth and progression. Previous studies have focused on the cancer cells, whereas, we provide compelling data, that in 95% of freshly harvested human colorectal cancers examined, functional GRPR is expressed by """"""""carcinoma-associated fibroblasts"""""""" (CAFs), not the malignant epithelial cells. BN treatment of these CAFs stimulates their proliferation, activates NF(B, and induces cyclooxygenase (COX2) in an MEK/ERK pathway-dependent manner. BN induces increased PGE2 release from CAFs and PGE2 stimulates the migration of colonic epithelial cells in vitro. The novel hypothesis of this proposal is that BN stimulates colorectal carcinogenesis, not by directly activating the colonic epithelial cell, but rather, indirectly, by activating the CAFs. To test this hypothesis, we will address the following two aims:
Aim 1 : To determine the mechanisms by which BN activates colorectal CAFs. We will examine BN-mediated CAF proliferation, activation of the MEK/ERK pathway, regulation of COX-2 promoter activity and upregulation of Hepatocyte Growth Factor in CAFs.
Aim 2 : To determine how BN-activated CAFs contribute to neoplastic progression and metastasis in colorectal cancer. We will compare the differences between normal fibroblasts, BN-activated CAFs, and their shRNA-GRPR knockdown counterparts when co-implanted with human colorectal cancer cells in murine xenograft and liver metastasis models. The short-term goal of this proposal is to identify mechanisms by which CAFs modulate the biology of tumor epithelial cells. Successful completion of these aims will advance the long-term goal of defining the role of Gl peptide hormones in regulating tumor progression by mediating stromal/epithelial interactions. Since only 8% of colorectal cancers examined actually harbor concomitant mutations of APC, K-ras, and p-53, additional epigenetic events, such as the overexpression of GRPR, in CAFs may be an additional consideration in the pathogenic alterations of colorectal cancer progression and metastasis. Targeting these cell surface receptors on CAFs, combined with anti-angiogenic and cytotoxic drugs, may provide an additional, rational therapeutic option. Finally, because we have shown that GRPR is an upstream activator of COX2 in CAFs in colon cancer, the study of signaling mechanisms by GRPR may elucidate methods of colon cancer prevention with fewer side effects.
Colon cancers aberrantly express gastrin-releasing peptide hormone (GRP) and its receptor (GRPR). Activation of this receptor controls genes which can increase tumor growth, motility, and secretion of enzymes that allow cancer cells to spread. We show that 95% of colon tumors express GRPR in supporting cells called fibroblasts, which interact with the colon cancer cells. By studying the relevant mechanisms, we may better design drugs to target GRPR in these supporting cells, and thus improve patient survival.
|Johnson, Paul; Beswick, Ellen J; Chao, Celia et al. (2016) Isolation of CD 90+ Fibroblast/Myofibroblasts from Human Frozen Gastrointestinal Specimens. J Vis Exp :e53691|
|Mrazek, Amy A; Porro, Laura J; Bhatia, Vandanajay et al. (2015) Apigenin inhibits pancreatic stellate cell activity in pancreatitis. J Surg Res 196:8-16|
|Almahariq, Muayad; Chao, Celia; Mei, Fang C et al. (2015) Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo. Mol Pharmacol 87:142-9|
|Hellmich, Mark R; Coletta, Ciro; Chao, Celia et al. (2015) The therapeutic potential of cystathionine Î²-synthetase/hydrogen sulfide inhibition in cancer. Antioxid Redox Signal 22:424-48|
|Mrazek, Amy A; Chao, Celia (2014) Surviving cutaneous melanoma: a clinical review of follow-up practices, surveillance, and management of recurrence. Surg Clin North Am 94:989-1002, vii-viii|
|Mrazek, Amy A; Carmical, Joseph R; Wood, Thomas G et al. (2014) Colorectal Cancer-Associated Fibroblasts are Genotypically Distinct. Curr Cancer Ther Rev 10:97-218|
|Chen, Haijun; Mrazek, Amy A; Wang, Xiaofu et al. (2014) Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorg Med Chem 22:3393-404|
|MÃ³dis, Katalin; Coletta, Ciro; Asimakopoulou, Antonia et al. (2014) Effect of S-adenosyl-L-methionine (SAM), an allosteric activator of cystathionine-Î²-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro. Nitric Oxide 41:146-56|
|Djukom, Clarisse; Porro, Laura J; Mrazek, Amy et al. (2014) Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression. Pancreas 43:88-92|
|Szabo, Csaba; Coletta, Ciro; Chao, Celia et al. (2013) Tumor-derived hydrogen sulfide, produced by cystathionine-Î²-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci U S A 110:12474-9|
Showing the most recent 10 out of 17 publications