SI‐CLP inhibits the growth of mouse mammary adenocarcinoma by preventing recruitment of tumor‐associated macrophages

Abstract

Chitinase‐like proteins (CLP) are chitin‐binding proteins that lack chitin hydrolyzing activity, but possess cytokine‐like and growth factor‐like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL‐40 and stabilin‐1 interacting chitinase‐like protein (SI‐CLP). Despite numerous reports indicating the role of YKL‐40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI‐CLP in cancer was not reported. Using gain‐of‐function approach, we demonstrate in the current study that the expression of recombinant SI‐CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor‐associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI‐CLP expressing tumors. Gene expression analysis in TAM isolated from SI‐CLP‐expressing and control tumors demonstrated that SI‐CLP does not affect macrophage phenotype. However, SI‐CLP significantly inhibited migration of murine bone‐marrow derived macrophages and human primary monocytes toward monocyte‐recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI‐CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI‐CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine‐induced TAM recruitment. Taking into consideration weak to absent expression of SI‐CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM‐mediated support of breast tumor growth.

New tools to prevent cancer growth and spread: a ‘Clever’ approach

“…54 Another Clever-1 ligand, stabilin-1-interacting chitinase-like protein (SI-CLP), inhibits tumour growth in a mouse breast cancer model by blocking the cytokine-induced recruitment of TAMs and altering the cell composition of the TME. 55 As the expression of SI-CLP has been reported to be markedly downregulated or absent in some human breast cancers, 55 targeting Clever-1 might again prove a worthwhile strategy.…”

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

“…These typical M2 markers are surface receptors that are responsible for the non-inflammatory clearance of microenvironment from apoptotic bodies, ECM components, soluble mediators of activation of cancer cells and angiogenesis (6)(7)(8)(9)(10)(11)(12). In addition to scavenging function (10,11,13), stabilin-1 acts as an intracellular sorting receptor that targets chitinase-like proteins SI-CLP and YKL-39 to the secretory pathway (14)(15)(16)(17)(18)(19). SI-CLP and YKL-39, in turn, regulate monocyte recruitment and angiogenesis (15,17,18,20).…”

“…In addition to scavenging function (10,11,13), stabilin-1 acts as an intracellular sorting receptor that targets chitinase-like proteins SI-CLP and YKL-39 to the secretory pathway (14)(15)(16)(17)(18)(19). SI-CLP and YKL-39, in turn, regulate monocyte recruitment and angiogenesis (15,17,18,20).…”

Tumor-Associated Macrophages: Key Players in Triple-Negative Breast Cancer

“…Blocking the effect of chemokines is an important method to inhibit the recruitment of TAMs, and the current research targets are mostly CCL2/CCR2 ( 52 , 111 ). The inhibition of the CCL2/CCR2 axis can reduce the mobilization of bone marrow mononuclear cells, thereby reducing the infiltration of macrophages in the breast ( 112 , 113 ). Studies have shown that trabectedine and bortezomib can inhibit the recruitment of macrophages by reducing the content of CCL2 in plasma ( 114 ).…”