Tumor‐stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7

Abstract

Recent studies have shown that stromal fibroblasts have a more profound influence on the initiation and progression of carcinoma than was previously appreciated. This study aimed at investigating the reciprocal relationship between cancer cells and their associated fibroblasts at both the molecular and cellular level in oral squamous cell carcinoma (OSCC). To identify key molecular regulators expressed by carcinoma-associated fibroblasts (CAF) that promote cancer cell invasion, microarrays were performed by comparing cocultured OSCC cells and CAF with monoculture controls. Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. Cytokine antibody array analysis of the supernatant from OSCC cell culture revealed that interleukin-1a was an inducer of CCL7 secretion by CAF. This study confirms the reciprocal relationship of the molecular crosstalk regulating the invasion of OSCC and describes new potential targets for future therapy.Carcinomas are malignant neoplasms derived from epithelial cells and are surrounded by specialized stroma, which orchestrate with cancer cells to regulate disease progression. 1-3 Carcinoma-associated fibroblasts (CAF) have been recognized as prominent modifiers of cancer initiation and progression. 4,5 For instance, it has been previously demonstrated that human prostatic CAF induce tumor formation from initiated but nontumorigenic human prostatic epithelial cells. 6 CAF also facilitate the invasiveness of otherwise noninvasive cancer cells when coinjected into mice. 7 The putative proinvasive effects of CAF may be mediated through either direct heterotypic cellÀcell contacts 8 or diffusible molecules, such as inflammatory mediators, cytokines and chemokines. 9,10 Chemokines have been shown to play an important role in tumor biology by influencing tumor growth, invasion and metastasis. 11 Chemokines are a family of small, structurally related cytokines with chemoattractant and activation properties that are involved in inflammatory reactions. 12 They are classified mainly into the CC and CXC subfamilies, according to the location of the first 2 cysteine residues, and are produced by a range of cell types, including fibroblasts. Various types of cancer cells also express chemokines and chemokine receptors, 11,[13][14][15] and their autocrine and paracrine roles in cancer progression are receiving increasing attention. For example, the CXC chemokine, CXCL12 (stromal cell-derived factor 1), secreted by CAF, r...

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

“…Fibroblast growth with tumor cells resulted in increased production of chemokines whose source was the CAFs themselves. Chemokines such as leptin produced under these 'mixed' conditions promoted tumor promalignancy activities (38)(39)(40). The bidirectional cross-talk between breast cancer cells and CAFs drives tumor progression via leptin signaling (37).…”

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…CCL7 also plays a role in various types of cancers, and this protein was previously found to be a strong chemotactic cytokine for multiple myeloma cells, which likely resulted from a specific homing function of this protein (55). Jung et al (56) reported that CCL7, which is induced by carcinoma-associated fibroblasts, significantly induced the ability of migration of oral squamous cells. Similarly, CCL7 was found to be positively correlated to invasion and metastasis and patient survival of gastric cancer (57).…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…However, the physiological origin of TNF-α in these studies was not defined. While it is conceivable that such paracrine signalling mechanisms that activate fibroblasts in vivo could be derived from immune cells, there is also evidence indicating direct regulation by neoplastic cells: co-culture of fibroblasts with either melanoma cells or oral squamous cell carcinoma cells induces pro-inflammatory gene expression in fibroblasts that includes CXCL1 and CXCL2 [59,60]. Activation of CAFs can also be accelerated by autocrine signalling: Kojima et al reported that autocrine TGF-β and SDF-1α/CXCL12 chemokine signalling result in activation of mammary CAFs, but the in vivo molecular signals that trigger these inflammatory pathways in CAFs remain unknown [61].…”