Abstract
Simple SummaryIn colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) promote tumor growth and progression through the synthesis of various molecules targeting the neoplastic cells. Here, we demonstrate that IL-34, a cytokine highly expressed in CRC tissue, regulates the function of CAFs in a paracrine and autocrine manner. Specifically, IL-34 induces normal fibroblasts (NFs) to acquire a cellular phenotype resembling that of CAFs, while IL-34 knockdown in CAFs reduces their tumorigenic properties and proliferation. Moreover, IL-34 stimulates NFs to produce netrin-1 and b-FGF—two factors that enhance CRC cell growth and migration. Altogether, our data support the involvement of IL-34 in CRC.The stromal compartment of colorectal cancer (CRC) is marked by the presence of large numbers of fibroblasts, termed cancer-associated fibroblasts (CAFs), which promote CRC growth and progression through the synthesis of various molecules targeting the neoplastic cells. Interleukin (IL)-34, a cytokine over-produced by CRC cells, stimulates CRC cell growth. Since IL-34 also regulates the function of inflammatory fibroblasts, we hypothesized that it could regulate the tumor promoting function of colorectal CAFs. By immunostaining and real-time PCR, we initially showed that IL-34 was highly produced by CAFs and to lesser extent by normal fibroblasts isolated from non-tumoral colonic mucosa of CRC patients. CAFs and normal fibroblasts expressed the functional receptors of IL-34. IL-34 induced normal fibroblasts to express α-SMA, vimentin and fibroblast activation protein and enhanced fibroblast growth, thus generating a cellular phenotype resembling that of CAFs. Consistently, knockdown of IL-34 in CAFs with an antisense oligonucleotide (AS) decreased expression of such markers and inhibited cell proliferation. Co-culture of CRC cells with IL-34 AS-treated CAFs supernatants resulted in less cancer cell proliferation and migration. Among CAF-derived molecules known to promote CRC cell growth/migration, only netrin-1 and basic-fibroblast growth factor were induced by IL-34. Data suggest a role for IL-34 in the control of colorectal CAF function.
Highlights
In carcinomas, neoplastic epithelial cells actively interact with various immune cells, stromal cells and endothelial cells, generating a microenvironment that fosters carcinogenetic processes.the tumor-associated stromal cells play a pivotal role in tumor initiation, progression, Cancers 2020, 12, 3537; doi:10.3390/cancers12123537 www.mdpi.com/journal/cancersCancers 2020, 12, 3537 drug resistance, and relapse of cancer [1]
The experiments were performed by comparing these pairs of cancer-associated fibroblasts (CAFs) and the corresponding normal fibroblasts, thereby avoiding bias due to inter-individual differences
By real-time PCR, we showed that IL-34 RNA transcripts were significantly increased in CAFs compared to the corresponding normal fibroblasts, and this result was confirmed by immunostaining (Figure 1B,C)
Summary
Cancers 2020, 12, 3537 drug resistance, and relapse of cancer [1] This has been shown, for instance, in colorectal cancer (CRC)—one of the most common cancers accounting for nearly 10% of cancer-related deaths worldwide [2]. Functional studies showed that such cells, termed cancer-associated fibroblasts (CAFs), promote malignant cell growth and metastasis through bidirectional signaling with both neoplastic cells and other cells within the tumor microenvironment [4,5]. Specific stromal gene profiles have been associated with resistance to chemotherapy and poor prognosis [6,7] Within the tumor microenvironment, both immune and non-immune cells synthesize various cytokines, which trigger specific signaling in fibroblasts, thereby instructing them to produce a pro-tumorigenic secretome [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
