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Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.

ABSTRACT: PURPOSE:Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca(2+)-dependent enzyme that cross-links proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma. EXPERIMENTAL DESIGN:Orthotopic pancreatic xenografts and coculture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. RESULTS:We show that TG2 secreted by cancer cells effectively molds the stroma by cross-linking collagen, which, in turn, activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells, leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells leads to decreased size of pancreatic xenografts. CONCLUSIONS:Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the cross-talk between cancer cells and stroma fundamentally affecting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.

SUBMITTER: Lee J

PROVIDER: S-EPMC4592394 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.

Lee Jiyoon J Condello Salvatore S Yakubov Bakhtiyor B Emerson Robert R Caperell-Grant Andrea A Hitomi Kiyotaka K Xie Jingwu J Matei Daniela D

Clinical cancer research : an official journal of the American Association for Cancer Research 20150603 19

<h4>Purpose</h4>Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca(2+)-dependent enzyme that cross-links proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma.<h4>Experimental design</h4>Orthotopic pancreatic xenografts and coculture systems tested the mechanis ...[more]

PMID: 26041746

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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:BackgroundDCLRE1B is a 5'-to-3' exonuclease, which is involved in repairing ICL-related DNA damage. DCLRE1B has been reported to cause poor prognosis in a variety of cancers. Nonetheless, there is no research on DCLRE1B's biological role in pan-cancer datasets. Thus, ascertaining the processes via which DCLRE1B modulates tumorigenesis was the goal of the extensive bioinformatics investigation of pan-cancer datasets in the present research.MethodsIn our research, employing internet websites and databases including TIMER, GEPIA, TISIDB, Kaplan-Meier Plotter, SangerBox, cBioPortal, and LinkedOmics, DCLRE1B-related data in numerous tumors were extracted. To ascertain the association among DCLRE1B expression, prognosis, genetic changes, and tumor immunity, the pan-cancer datasets were examined. The DCLRE1B's biological roles in pancreatic cancer cells were ascertained by employing wound healing, in vitro CCK-8, and MeRIP-qPCR assays.ResultAccording to the pan-cancer analysis, in numerous solid tumors, DCLRE1B upregulation was observed. Expression of DCLRE1B was found to be substantially related to the cancer patients' prognoses. Similarly, expression of DCLRE1B exhibited substantial association with immune cells in several cancer types. DCLRE1B expression correlated with immune checkpoint (ICP) gene expression and impacted immunotherapy sensitivity. According to in vitro trials, DCLRE1B promoted PC cells' proliferation and migration capacities. Also, according to GSEA enrichment analysis, DCLRE1B might participate in the JAK-STAT signaling pathway, which was confirmed by western blotting. In addition, we also found that the downregulation of DCLRE1B may be regulated by METTL3-mediated m6A modification.ConclusionsIn human cancer, the overexpression of DCLRE1B was generally observed, which aided cancer onset and advancement via a variety of processes comprising control of the immune cells' tumor infiltration. According to this study's findings, in a few malignant tumors, DCLRE1B is a candidate immunotherapeutic and prognostic biomarker.

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Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.

Publications

Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.

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