Abstract
Colorectal cancer (CRC) is one of the three leading causes for cancer mortality. CRC kills over 600,000 people annually worldwide. The most common cause of death from CRC is the metastasis to distant organs. However, biomarkers for CRC metastasis remain ill-defined. We compared primary and metastatic CRC cell lines for their angiogenesis-protein profiles and intracellular signaling profiles to identify novel biomarkers for CRC metastasis. To this end, we used primary and metastatic CRC cell lines as a model system and normal human colon cell line as a control. The angiogenesis profiles two isogenic CRC cell lines, SW480 and SW620, and HT-29 and T84 revealed that VEGF was upregulated in both SW620 and T84 whereas coagulation factor III, IGFBP-3, DPP IV, PDGF AA/AB, endothelin I and CXCL16 were downregulated specifically in metastatic cell lines. Furthermore, we found that TIMP-1, amphiregulin, endostatin, angiogenin were upregulated in SW620 whereas downregulated in T84. Angiogenin was downregulated in T84 and GM-CSF was also downregulated in SW620. To induce CRC cell metastasis, we treated cells with pro-inflammatory cytokine IL-6. Upon IL-6 treatment, epithelial-mesenchymal transition was induced in CRC cells. When DLD-1 and HT-29 cells were treated with IL-6; Akt, STAT3, AMPKα and Bad phosphorylation levels were increased. Interestingly, SW620 showed the same signal activation pattern with IL-6 treatment of HT-29 and DLD-1. Our data suggest that Akt, STAT3, AMPKα and Bad activation can be biomarkers for metastatic colorectal cancer. IL-6 treatment specifically reduced phosphorylation levels of EGFR, HER2 receptor, Insulin R and IGF-1R in receptor tyrosine kinase array study with HT-29. Taken together, we have identified novel biomarkers for metastatic CRC through the angiogenesis-antibody array and intracellular signaling array studies. Present study suggests that those novel biomarkers can be used as CRC prognosis biomarkers, and as potential targets for the metastatic CRC therapy.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide, accounting for approximately 608,000 deaths worldwide [1]
Metastasis occurs in a phase of tumor progression by metastatic variant cells that possess invasive activities characterized by increased cell migration, tissue invasion, and organ colonization
Specific angiogenesis signature proteins are downregulated in metastatic CRC cell lines of SW620 and T84
Summary
Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide, accounting for approximately 608,000 deaths worldwide [1]. Over the last four decades, significant efforts have been made to characterize useful biomarkers for CRC [3,4,5]. There are no valuable biomarkers for CRC metastasis. It is essential to identify novel biomarkers that can be used to predict the metastatic potential of CRC, serve as prognostic indicators and serve as cellular targets for the targeted-therapy on CRC. We have utilized the angiogenesis-related antibody arrays with primary and metastatic CRC cell lines to identify and characterize the novel biomarkers associated with colorectal cancer metastasis
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