Cytokine signaling regulating adipose stromal cell trafficking

Abstract

Adipocyte progenitors, known as adipose stromal cells (ASC), can become mobilized, recruited by tumors, and contribute to cancer progression. Mechanisms underlying ASC trafficking have remained obscure. We recently reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing CXCR1 in obesity. As a candidate mechanism of CXCL1 activation, we identified interleukin (IL)-22, systemic circulation of which is increased in obesity. It has been reported that IL-22 signaling through IL-22R is upstream of CXCL1. Here, we provide evidence that IL-22 expression by leukocytes infiltrating WAT and IL-22R expression by tumors is obesity-dependent. We propose that obesity-associated adipocyte death and the resulting recruitment of leukocytes triggers the IL-22 signaling cascade that induces CXCL1 secretion by cancer cells responsible for ASC trafficking to tumors. KEYWORDS adipose stromal cell; cytokine; chemokine; CXCL1; cancer; interleukin-22; receptor; obesity Epidemiology studies have indicated that progression of many cancers is associated with obesity. 1-5 Excess white adipose tissue (WAT) directly contributes to disease progression, alongside with obesity-associated lifestyle and diet. 6,7 Our studies using mouse models have shown that excess of WAT, which is overgrown in obese individuals, promotes tumor growth irrespective of diet used to induce obesity. 8,9 WAT is composed by adipocytes and vascular/stromal cells. 10,11 Adipose stromal cells (ASC) serve as the mesenchymal progenitors of adipocytes and as endothelium-supporting perivascular cells 12-14 with potent angiogenic capacity. 15 While malignant cells with ASC properties comprise an integral component of liposarcomas, tumors derived from WAT, 16 it is benign ASC that promote carcinoma progression. Along with other WAT cells, ASC secrete hormones, inflammatory cytokines, and growth factors collectively termed adipokines, many of which have pro-tumorigenic properties. 17,18 It has been discovered that, like bone marrow mesenchymal stem cells (MSC), 19 ASC can become mobilized and traffic outside WAT. [20][21][22] Because numbers of ASC increase in obesity, we had hypothesized that WAT is a contributor to the pool of tumor stromal cells. 23,24 We have identified ASC trafficking to tumors as the mechanism underlying the obesity-cancer link. In animal studies, administered ASC engraft tumors, which results in accelerated cancer progression. 8,9,[25][26][27] Our findings confirmed by data from other laboratories demonstrate tumor homing of endogenous ASC in obesity, which is concomitant with increased vascularization and adipogenesis promoting survival and proliferation of neighboring malignant cells. [28][29][30][31][32] The apparent contribution of ASC to the tumor stroma has raised a question regarding the safety of lipotransfer procedures in cancer patients. 33,34 Specific molecular mechanisms through which ASC promote cancer are being investigated, and it is becoming apparent that paracrine factors secreted by ASC within the tumor larg...

Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer

“…Adipose stromal cells (ASCs), which are adipocyte progenitors within fatty tissue, have been implicated in the development of these cancers (7,8). While released factors from abdominal fat can be transported systemically, identification of circulating ASCs in obese subjects and recruitment of these cells by tumor-produced chemokines suggest that ASCs are trafficked to target tissue sites and embedded within the tumor microenvironment (9–12).…”

PAI-1-Dependent Inactivation of SMAD4-Modulated Junction and Adhesion Complex in Obese Endometrial Cancer

“…ASCs derived from adipose tissues, including the parametrial fat near the uterus, can be mobilized via chemokine actions to the endometrial microenvironment and promote epithelial tumorigenesis ( Ma et al, 2016 ; Zhang et al, 2010 ; Zhang and Kolonin, 2016 ). These adipocyte progenitors exert paracrine actions by secreting abundant PAI-1 and other factors that may alter signaling responses in nearby EECs.…”

Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences

“…The poor survival of obese patients with prostate cancer has been linked to ASC trafficking from WAT to tumors, which is mediated by CXCL1 that is secreted from malignant epithelium and signaling on ASC via its receptor CXCR1 [138]. It was also found that the secretion of CXCL1 by tumors in the setting of obesity is induced by WAT leukocyte-derived interleukin IL-22 signaling through IL-22R on cancer cells [152].…”