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Neutralizing murine TGF?R2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.

ABSTRACT: Elevated levels of TGF? are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGF? pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGF? remains challenging because TGF? has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGF? promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGF? receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGF? signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGF?-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 4996-5007. ©2014 AACR.

SUBMITTER: Ostapoff KT

PROVIDER: S-EPMC4167492 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.

Ostapoff Katherine T KT Cenik Bercin Kutluk BK Wang Miao M Ye Risheng R Xu Xiaohong X Nugent Desiree D Hagopian Moriah M MM Topalovski Mary M Rivera Lee B LB Carroll Kyla D KD Brekken Rolf A RA

Cancer research 20140724 18

Elevated levels of TGFβ are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFβ pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFβ remains challenging because TGFβ has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFβ promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that ...[more]

PMID: 25060520

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Project description:Rationale: The peripheral nervous system (PNS) plays an important role in tumor growth and progression. Schwann cells (SCs), the main glia cells of the PNS, augment cancer metastasis in contact-dependent or contact-independent manner in various malignancies. In the present study, we aimed to determine whether interplay between pancreatic cancer cells and SCs via paracrine signaling contributes to cancer progression. Methods: Immunofluorescence analysis was performed to reveal the distribution of SCs in PDAC tissues and to determine the prognostic value and clinicopathological relevance of the level of intra‑tumoral SC markers for patients diagnosed with PDAC. Transwell assays and wound healing assays were carried out to investigate the influence of SC conditioned medium (SCM), SC co‑culture, or co-cultured CM on the migratory and invasive abilities of pancreatic cancer cells. The mechanism of SCs induced cancer cells migration and invasion was confirmed using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assays (ELISAs), western blotting, immunofluorescence, immunohistochemistry, siRNA-mediated gene interference, and an in vivo mouse model. Results: Immunofluorescence analysis of tissue samples revealed that there were two different types of SCs distributed in the tumor microenvironment, the presence of which correlated with several clinicopathological characteristics and overall survival for patients with PDAC. Although SCM had no impact on the motility and invasiveness of tumor cells, both co-cultivation with SCs and co‑cultured CM enhanced pancreatic cancer cell migration and invasion. Mechanistically, SC‑derived Interleukin 6 (IL6), which was induced by co-culture with pancreatic cancer cells, augmented cancer cell migration and invasion by activating STAT3 signaling in cancer cells, while IL6 neutralization or STAT3 downregulation abrogated these effects. Furthermore, Interleukin 1β (IL1β), secreted by tumor cells, activated the nuclear actor (NF)-kappa B pathway in SCs, resulting in increased cytokines production, including IL6, while inhibiting the IL1β-IL1R1 axis led to inactivation of NF-kappa B signaling and downregulated cytokines expression in SCs. Interfering with tumor-neuroglia crosstalk impeded cancer cell dissemination in vivo. Conclusion: Schwann cells were extensively distributed in the PDAC tumor microenvironment and high level of intra-tumoral SC markers could serve as an independent prognostic factor for poor survival of patients with PDAC. The tumor-neuroglia interaction is indispensable for SCs to acquire a tumor-facilitating phenotype. Targeting the tumor-neuroglia interplay might be a promising strategy to treat PDAC.

Project description:BackgroundPancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-β2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis.MethodsIn vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual-luciferase reporter assays were accordingly used to detect miR-193a and TGF-β2/TGF-βRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR-193a antagonist on pancreatic cancer repopulation and metastasis after radiation.ResultsmiR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR-193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-β2/TGF-βRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-β2/TGF-βRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-β2/TGF-βRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation.ConclusionsOur findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis.

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Neutralizing murine TGF?R2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.

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Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.

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