Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis

Abstract

The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL-13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL-13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…In line with these findings, there was decreased primary mammary tumor growth and pulmonary metastasis with an increase in survival in YKL-40/CHI3L1 KO mice bearing mammary tumors [31]. With the use of a melanoma metastasis model, Ma et al [32] have shown that there is decreased metastasis to the lungs in the YKL-40/ CHI3L1 KO mice. In spite of all of the evidence in the mouse models and studies correlating YKL-40/CHI3L1 expression in patients with various cancers, to date, there is no clear-cut evidence in published studies to indicate clinically that CHI3L1 is linked to inflammation-associated cancer development or metastasis.…”

“…Ma et al [32] demonstrated that a known decoy receptor of IL-13, IL-13Ra2, functions as a receptor for YKL-40/ CHI3L1. In comparing cell death of immune cells in wild-type with YKL-40/CHI3L1 KO mice, Lee et al [37] showed increased cell death in CD4 + T cells, macrophages, and eosinophils in the KO mice, indicating that YKL-40/CHI3L1 is anti-apoptotic.…”

“…Recent studies indicated that IL-13Ra2 plays a role in melanoma lung metastasis. A comparison of WT and IL-13Ra2 KO mice showed decreased metastasis to the lungs in IL-13Ra2 KO mice [32]. He et al [38] evaluated whether YKL-40/CHI3L1 mediated its metastatic effects via IL-13Ra2 and subsequent production of TGF-b1 using a melanoma model.…”

Circulating tumor cell interactions with macrophages: implications for biology and treatment

“…CHI3L1 is expressed by a range of normal cells, including macrophages, neutrophils, epithelial cells, smooth muscle cells, and chondrocytes, and its expression is enhanced by a number of cytokines, including IL13, IL6, IL1β, and IFNγ (98,99). Increased serum levels of CHI3L1 have been associated with a negative prognosis in nonmalignant diseases such as inflammation and asthma (99,100).…”

“…The ability of CHI3L1 to bind heparan sulfates allows its interaction with cell surface proteoglycan syndecan-1, resulting in VEGF production and enhanced angiogenesis in glioblastoma (110). Lung metastasis of melanoma and breast cancer cells was reduced after blocking ChI3L1 with antibodies or removing its regulator semaphorin 7a in experimental animals (98). Treatment with chitin microparticles inhibited tumor growth and angiogenesis at primary tumor sites but also reduced metastasis to the lung (106,111).…”