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...

Recurrence of EGC after curative resection can be predicted by using common clinical characteristics. Patients at high risk of overall and early recurrence could be identified; individual disease-free survival was predictable by the internally validated nomogram.

BackgroundDue to improved survival rate, gastric cancer (GC) patients have an increased risk of developing multiple primary cancer (MPC). The purpose of this study is to evaluate the clinicopathological features of MPC and to generate useful tools for the prediction of metachronous MPC following gastrectomy.Methods3066 patients who underwent curative resection of GC were reviewed retrospectively, based on the clinical information and the medical record.ResultsThe 5-year incidence of MPC was 2.5%. Of these, 54.3% had a metachronous MPC, while 45.7% had a synchronous MPC. The most prevalent site of metachronous MPC was the colorectum (26.3%), followed by lung (23.7%) and liver (18.4%). Multivariate logistic regression analysis revealed that old age at the time of GC diagnosis (≥60 years), early stage of GC (stage I and II), and multiplicity of GC at the time of gastrectomy were independent predictive factors for metachronous MPC. GC patients with either metachronous or synchronous MPC showed poorer survival than patients without MPC. In addition, patients with a metachronous MPC showed late survival disadvantage, while patients with a synchronous MPC showed early survival disadvantage. Furthermore, we were able to develop and internally validate a nomogram to predict the metachronous MPC after curative gastrectomy (C-index = 0.72).ConclusionPatients at high risk of developing metachronous MPC after curative resection of GC were identified. Individual risk of developing metachronous MPC could be predicted by a novel nomogram. Further external validation with independent patient cohorts is required to improve the accuracy of prediction.

Molecular crosstalk between cancer cells and fibroblasts has been an emerging hot issue in understanding carcinogenesis. As oral submucous fibrosis (OSF) is an inflammatory fibrotic disease that can potentially transform into squamous cell carcinoma, OSF has been considered to be an appropriate model for studying the role of fibroblasts during early stage carcinogenesis. In this sense, this study aims at investigating whether areca nut (AN)‐exposed fibroblasts cause DNA damage of epithelial cells. For this study, immortalized hNOF (hTERT‐hNOF) was used. We found that the levels of GRO‐α, IL‐6 and IL‐8 increased in AN‐exposed fibroblasts. Cytokine secretion was reduced by antioxidants in AN‐exposed fibroblasts. Increase in DNA double strand breaks (DSB) and 8‐oxoG FITC‐conjugate was observed in immortalized human oral keratinocytes (IHOK) after the treatment of cytokines or a conditioned medium derived from AN‐exposed fibroblasts. Cytokine expression and DNA damage were also detected in OSF tissues. The DNA damage was reduced by neutralizing cytokines or antioxidant treatment. Generation of reactive oxygen species (ROS) and DNA damage response, triggered by cytokines, were abolished when NADPH oxidase (NOX) 1 and 4 were silenced in IHOK, indicating that cytokine‐triggered DNA damage was caused by ROS generation through NOX1 and NOX4. Taken together, this study provided strong evidence that blocking ROS generation might be a rewarding approach for cancer prevention and intervention in OSF.

Survival in OSCC can be predicted more accurately by using biomarkers. The constructed nomogram predicted survival after treatment for an individual patient with OSCC, and it can be practically used as a tool to help decide which adjuvant treatment is most appropriate.