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Article

HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer

1
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy
2
Department of Oncology, University of Turin, 10060 Candiolo, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Guido Eibl
Cancers 2021, 13(14), 3519; https://doi.org/10.3390/cancers13143519
Received: 30 April 2021 / Revised: 30 June 2021 / Accepted: 10 July 2021 / Published: 14 July 2021
It has been previously shown that activation of the MET receptor by its ligand, the hepatocyte growth factor (HGF), modulates the tumor-stroma cross-talk in models of pancreatic cancer. We now wish to cast light on the molecular mechanisms by which this ligand/receptor pair sustains the interaction between cancer cells and the tumor microenviroment. To this end, we compared data obtained by large-scale analysis of gene expression in pancreatic cancer cells grown in the presence of HGF versus cells grown in the presence of HGF and treated with specific inhibitors of HGF/MET signaling. By clustering differentially expressed genes according to functional groups, we identified candidate genes involved in the process. Among these, tenascin C was selected due to its activity in sustaining the malignant phenotype. Our results highlight a new role for tenascin C, which could represent the operative arm through which MET promotes activation of the stromal compartment in pancreatic cancer.
Pancreatic ductal adenocarcinoma is an aggressive tumor characterized by the presence of an abundant stromal compartment contributing significantly to the malignant phenotype. Pancreatic stellate cells are peculiar fibroblasts present in the stroma and represent the predominant source of extracellular matrix proteins, pro-inflammatory cytokines, and growth factors, including hepatocyte growth factor (HGF). Exploiting a co-culture system of human pancreatic stellate cells and cancer cells, we demonstrated that fibroblast activation was reduced upon HGF/MET axis inhibition. To unveil the signaling pathways sustaining stroma modulation orchestrated by MET activation in the tumor, we analyzed the gene expression profile in pancreatic cancer cells stimulated with HGF and treated with HGF/MET inhibitors. Transcriptome analysis showed that, among all the genes modulated by HGF, a subset of 125 genes was restored to the basal level following treatment with the inhibitors. By examining these genes via ingenuity pathway analysis, tenascin C emerged as a promising candidate linking MET signaling and tumor microenvironment. MET-dependent tenascin C modulation in pancreatic cancer cells was validated at RNA and protein levels both in vitro and in vivo. In conclusion, this work identifies tenascin C as a gene modulated by MET activation, suggesting a role in MET-mediated tumor-stroma interplay occurring during pancreatic tumor progression. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; tumor microenvironment; hepatocyte growth factor; MET oncogene; tenascin C; metastasis pancreatic ductal adenocarcinoma; tumor microenvironment; hepatocyte growth factor; MET oncogene; tenascin C; metastasis
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MDPI and ACS Style

Modica, C.; Olivero, M.; Zuppini, F.; Milan, M.; Basilico, C.; Vigna, E. HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer. Cancers 2021, 13, 3519. https://doi.org/10.3390/cancers13143519

AMA Style

Modica C, Olivero M, Zuppini F, Milan M, Basilico C, Vigna E. HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer. Cancers. 2021; 13(14):3519. https://doi.org/10.3390/cancers13143519

Chicago/Turabian Style

Modica, Chiara, Martina Olivero, Francesca Zuppini, Melissa Milan, Cristina Basilico, and Elisa Vigna. 2021. "HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer" Cancers 13, no. 14: 3519. https://doi.org/10.3390/cancers13143519

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