A role for cancer‐associated fibroblasts in inducing the epithelial‐to‐mesenchymal transition in human tongue squamous cell carcinoma

Tao

et al. 2016

J Exp Clin Cancer Res

BackgroundHyaluronan synthases (HAS) control the biosynthesis of hyaluronan (HA) and critically modulate the tumor microenviroment. Cancer-associated fibroblasts (CAFs) affect the progression of a tumor by remolding the matrix. However, little is known about the role of HAS from CAFs in this process. This study aimed to determine the role of hyaluronan synthase 2 (HAS2) from CAFs in the progression of oral squamous cell carcinoma (OSCC) invasion.MethodsHAS isoforms 1, 2, and 3 in paired sets of CAFs and normal fibroblasts (NFs) were examined by real-time PCR, and the expression of HAS2 and α-SMA in OSCC tissue sections was further evaluated using immunohistochemical staining. Furthermore, we used a conditioned culture medium model to evaluate the effects of HAS2 from CAFs on the invasion and epithelial-mesenchymal transition (EMT) of the oral cancer cells Cal27. Finally, we compared the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between CAFs and NF, and between CAFs with or without HAS2 knockdown using an antibody array and western blotting.ResultsCAFs expressed higher levels of HAS2 than the paired NFs. HAS2 expression was consistent with α-SMA-positive myofibroblasts in the stroma of OSCC, and these were significantly correlated advanced clinical stages and cervical lymph node metastasis. Knocking down HAS2 with a specific siRNA or treatment with a HAS inhibitor markedly attenuated CAF-induced invasion and EMT of Cal27 cells. Higher MMP1 and lower TIMP1 levels were detected in the supernatants of CAFs relative to NFs. Knocking down HAS2 could decrease the expression of MMP1 and increase that of TIMP1 in CAFs.ConclusionsHAS2 is one of the key regulators responsible for CAF-mediated OSCC progression and acts by modulating the balance of MMP1 and TIMP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0458-0) contains supplementary material, which is available to authorized users.

Section: Resultsmentioning

confidence: 99%

Hyaluronan synthase 2 expressed by cancer-associated fibroblasts promotes oral cancer invasion

Tao

et al. 2016

J Exp Clin Cancer Res

“…Studies indicate that paracrine interaction between CAFs and tumor cells could induce EMT and EMT-driven CSC properties and aggressive potency [45]. Giannoni et al identify a circuitry in which cancer cell-derived IL-6 activates fibroblasts, which in turn secrete matrix metalloproteinases (MMPs) to elicit EMT and enhance cancer stemness in prostate cancer cells, thereby culminating in tumor formation and spontaneous lung metastatic growth [46].…”

Section: Cafs Induce the Cancer Stem Cell Phenotypementioning

confidence: 99%

Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts

et al. 2015

Tumor microenvironment is composed of all the untransformed elements in the vicinity of tumor, mainly including a large number of stromal cells and extracellular matrix proteins, which play an active role in most solid tumor initiation and progression. Carcinoma-associated fibroblasts (CAFs), one of the most common stromal cell types in the tumor microenvironment, have been demonstrated to be involved in tumor growth, invasion, and metastasis. Therefore, they are becoming a promising target for anti-cancer therapies. In this review, we firstly summarize the current understandings of CAFs' molecular biology, including the heterogeneous cellular origins and molecular markers, and then, we focus on reviewing their various tumor-promoting phenotypes involved in complex mechanisms, which can be summarized to the CAF-conveyed paracrine signals in tumor cells, cancer stem cells, and metastasis-initiating cancer cells, as well as the CAF-enhanced extrinsic tumor-promoting processes including angiogenesis, extracellular matrix remodeling, and tumor-related inflammation; finally, we describe the available directions of CAF-based target therapy and suggest research areas which need to be further explored so as to deepen the understanding of tumor evolution and provide new therapeutic targets for cancer treatment.

Archives of Pathology &Amp; Laboratory Medicine

“…267 The mechanism of stimulation of tumor cell invasion by cancer-associated fibroblasts can include induction of EMT. 245,268 In several studies, a paracrine interaction between tumor cells and fibroblasts has been shown to stimulate invasion. For example, CCL2 from fibroblasts can stimulate invasion and reactive oxygen species production by tumor cells, which, in turn, stimulates fibroblast senescence and CCL2 production from the fibroblasts.…”

Section: Tumor Microenvironment and Invasionmentioning

confidence: 99%

“…[234][235][236][237] Myofibroblasts and cancerassociated fibroblasts have been shown to enhance HNSCC invasion in vitro in a variety of assays. [238][239][240][241][242][243][244][245][246][247] Treatments that can enhance the ability of fibroblasts to stimulate tumor cell invasion include irradiation 182 and reactive oxygen species, 183,248,249 as well as lifestyle-correlated factors, such as cigarette smoke 250 and areca nut extract. 251 Fibroblasts have been shown to stimulate tumor cell invasion through secretion of a number of factors, including chemokine (C-C motif) ligand 2 (CCL2), 183,252 260 and hepatocyte growth factor (HGF).…”

Section: Tumor Microenvironment and Invasionmentioning

confidence: 99%

Mechanisms of Invasion in Head and Neck Cancer

Jimenez¹,

Jayakar²,

Ow³

et al. 2015

Context.-The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed.Objectives.-To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion.Data Sources.-A literature review of peer-reviewed articles in PubMed on HNSCC invasion.Conclusions.-Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.