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TNF-? augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma.

ABSTRACT: Within the tumour microenvironment, a complex network of chemokines and their receptors affects the initiation and progression of tumours. The higher levels of tumour necrosis factor-alpha (TNF-?) are associated with tumour progression and an anti-TNF-? monoclonal antibody has been used successfully to treat patients with renal cell carcinoma (RCC). However, the role of chemokines and their receptors in the TNF-?-promoted progression of RCC remains unclear. In this study, TNF-? was found to enhance the migration, invasion and epithelial-mesenchymal transition (EMT) of RCC cells. To further investigate the molecular mechanism of TNF-? on the progression of RCC, reverse transcription and quantitative PCR was used to screen chemokines and chemokine receptors that were associated with tumorigenesis. The results showed that TNF-? significantly increased the expressions of CXCR2 and CXCR3 and their related ligands in RCC cells. Subsequently, we used a lentiviral shRNA system to knockdown the expression of CXCR2 and/or CXCR3 in RCC cells. CXCR2 and CXCR3 silencing inhibited the induction of Slug and ZEB-1 with TNF-? treatment of RCC cells. In addition, the knockdown of both CXCR2 and CXCR3 resulted in a greater decrease in cell migration, invasion and clonogenic ability compared with either CXCR2 or CXCR3 knockdown alone. Moreover, CXCR2 and CXCR3 silencing significantly reduced the sphere-forming ability of RCC cells. High expression levels of CXCR2 and CXCR3 in cancer tissues correlated with tumour progression of renal cell carcinoma. These findings suggest that TNF-? augments CXCR2 and CXCR3 to promote the progression of renal cell carcinoma leading to a poor prognosis.

SUBMITTER: Sun KH

PROVIDER: S-EPMC5082409 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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TNF-α augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma.

Sun Kuang-Hui KH Sun Guang-Huan GH Wu Yi-Ching YC Ko Bai-Jiun BJ Hsu Hui-Tzu HT Wu Sheng-Tang ST

Journal of cellular and molecular medicine 20160614 11

Within the tumour microenvironment, a complex network of chemokines and their receptors affects the initiation and progression of tumours. The higher levels of tumour necrosis factor-alpha (TNF-α) are associated with tumour progression and an anti-TNF-α monoclonal antibody has been used successfully to treat patients with renal cell carcinoma (RCC). However, the role of chemokines and their receptors in the TNF-α-promoted progression of RCC remains unclear. In this study, TNF-α was found to enha ...[more]

PMID: 27297979

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Project description:BackgroundAdoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer.MethodsBlood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays.ResultsWe detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells.ConclusionsTo increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells.

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TNF-? augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma.

Publications

TNF-α augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma.

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