Abstract
Colorectal cancer (CRC) is the most common malignancy worldwide, and its underlying molecular mechanisms remain largely unexplored. Accumulating evidences indicate cancer-associated fibroblasts (CAFs), abundant stromal cell population in the tumor microenvironment, play a key role in tumor development. Herein, we have successfully isolated CAFs and paired normal fibroblasts (NFs) from colorectal cancer tissues (n=10). By using a multiplex cytokine profiling assay, we have identified IL-6 as a major cytokine released by CAFs. Co-culturing of CAFs with CRC cell lines HCT116 or SW480 increases IL-6 release, and the secretion by CAFs can be further enhanced under hypoxia. By using the CCK-8 assay, we have found that HCT116 or SW480 cells treated with culture medium from CAFs, IL-6, or hypoxia showed a significant cell growth compared to control cells (p<0.01). Mechanistically, we have found that hypoxia could enhance the effect of the IL-6/STAT3 signaling on CRC cells, in part, through HIF-1a targeting PKM2. In conclusion, our data clearly proposes the interconnected mechanisms for constitutive activation of STAT3 signal by CAFs-derived IL-6 under hypoxia in colorectal cancer. The pharmacological inhibition of STAT3, PKM2, or HIF-1α can significantly reduce the oncogenic effect of IL-6, providing a potential therapeutic target for CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies in the world[1]
Cancer-associated fibroblasts (CAFs) act as major stromal cells to promote development of colorectal cancer, we hypothesized that CAFs is likely to release several key cytokines that links to the development of CRC
We investigated whether CAF-derived IL-6 can affect CRC cell growth in vitro
Summary
Colorectal cancer (CRC) is one of the most common malignancies in the world[1]. The environment or genetic factors have been hypothesized to influence tumorigenesis of CRC. The driven mechanism(s) for promoting development of CRC remains largely unexplored[2]. Tumor microenvironment (TME) has been demonstrated to play a key role in colorectal carcinogenesis[3]. TME is a composed of different components, including immune cells, fibroblasts, macrophage, endothelial cells and extracellular matrix (ECM)(4). It is increasingly appreciated that the tumor stroma is an integral part of cancer initiation, growth and progression. Colorectal cancer (CRC) is most common malignancy worldwide, and its underlying molecular mechanisms remain largely unexplored. Accumulating evidences indicate Cancer-Associated Fibroblasts (CAFs), abundant stromal cell population in the tumor microenvironment, play a key role in tumor development
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