Interleukin-34 sustains pro-tumorigenic signals in colon cancer tissue

Abstract

Interleukin-34 (IL-34), a cytokine produced by a wide range of cells, binds to the macrophage colony-stimulating factor receptor (M-CSFR-1) and receptor-type protein-tyrosine phosphatase zeta (PTP-z) and controls myeloid cell differentiation, proliferation and survival. various types of cancers over-express IL-34 but the role of the cytokine in colorectal cancer (CRC) remains unknown. We here investigated the expression and functional role of IL-34 in CRC. A more pronounced expression of IL-34 was seen in CRC samples as compared to matched normal/benign colonic samples and this occurred at both RNA and protein level. Immunohistochemical analysis of CRC tissue samples showed that both cancer cells and lamina propria mononuclear cells over-expressed IL-34. Additionally, CRC cells expressed both M-CSFR-1 and PTP-z, thus suggesting that CRC cells can be responsive to IL-34. Indeed, stimulation of DLD-1 cancer cells with IL-34, but not with MSCF1, enhanced the cell proliferation and cell invasion without affecting cell survival. Analysis of intracellular signals underlying the mitogenic effect of IL-34 revealed that the cytokine enhanced activation of ERK1/2 and pharmacologic inhibition of ERK1/2 abrogated IL-34-driven cell proliferation. Consistently, IL-34 knockdown in HT-29 cells with a specific IL-34 antisense oligonucleotide reduced ERK1/2 activation, cell proliferation and enhanced the susceptibility of cells to Oxaliplatin-induced death. This is the first study showing up-regulation of IL-34 in CRC and suggesting a role for this cytokine in colon tumorigenesis.

Interleukin-34, a comprehensive review

“…Since IL‐34 is expressed at mRNA level in various tissues, this expression is expected to be changed under pathological conditions. Indeed, several studies have confirmed the enhancement of IL‐34 expression at mRNA and protein levels in the context of various diseases including autoimmune disorders, inflammation, infections, metabolic diseases, neurological disorders, and cancer . At the cellular level, IL‐34‐producing cells include synovial fibroblasts, immune cells, epithelial cells, endothelial cells, adipocytes, and cancer cells.…”

“…Furthermore, IL‐34 induces STAT3 activation and miRNA‐21 increment in synovial fibroblast, resulting in increased resistance of fibroblast to apoptosis in RA . In an autocrine manner, IL‐34 provides a critical survival signal to CSF‐1R‐expressing cancer cells by enhancing activation of ERK1/2 and AKT signaling pathways and thus contributes to chemoresistance such as in lung and colon cancer cells in addition to malignant pleural mesothelioma cells . On the other hand, IL‐34 can inhibit the proliferation in other cells such as glioblastoma cells via a PTP‐ζ‐dependent mechanism …”

“…In this regard, accumulating evidence has unveiled the importance of IL‐34:CSF‐1R axis in cancer chemoresistance. CSF‐1R is expressed in a subset of cancer cells or can be induced upon exposure to chemotherapeutic agents . Similarly, IL‐34 is expressed in various types of cancer cells and can be induced by chemotherapy treatment .…”

“…CSF‐1R is expressed in a subset of cancer cells or can be induced upon exposure to chemotherapeutic agents . Similarly, IL‐34 is expressed in various types of cancer cells and can be induced by chemotherapy treatment . In an autocrine fashion, cancer cell‐derived IL‐34 induces strong activation of ERK1/2 and AKT downstream of CSF‐1R, thus providing CSF‐1R‐expressing cancer cells with a critical survival signaling that help them to survive under strict chemotherapeutic conditions, such as in pemetrexed‐treated pleural malignant mesothelioma cells, doxorubicin‐ or cisplatin‐treated lung cancer cells, and oxaliplatin‐treated colon cancer cells .…”

“…As an important factor that increases TAMs frequencies and enhances their pro‐tumorigenic functions, targeting IL‐34 has a therapeutic potential in TAMs‐targeting strategies . Furthermore, since cancer cells rely on IL‐34‐activated signaling pathways for their survival under chemotherapeutic conditions, targeting IL‐34 may help to sensitize therapeutic‐resistant cancer cells to cancer therapy such in chemoresistant lung cancers, colon cancers, and malignant pleural mesotheliomas . Finally, neutralizing IL‐34 may show therapeutic benefits in controlling tumor growth, cancer‐induced osteoclastogenesis, suppressing angiogenesis, and inhibiting cancer cell invasion and metastasis.…”