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Tumor microenvironment participates in metastasis of pancreatic cancer.

ABSTRACT: Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial-mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival.

SUBMITTER: Ren B

PROVIDER: S-EPMC6065152 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Tumor microenvironment participates in metastasis of pancreatic cancer.

Ren Bo B Cui Ming M Yang Gang G Wang Huanyu H Feng Mengyu M You Lei L Zhao Yupei Y

Molecular cancer 20180730 1

Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic can ...[more]

PMID: 30060755

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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.

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Tumor microenvironment participates in metastasis of pancreatic cancer.

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Tumor microenvironment participates in metastasis of pancreatic cancer.

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