Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness - PubMed (original) (raw)

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Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness

Simone Brivio et al. World J Hepatol. 2017.

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma (TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS (myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors (cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix (ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells (as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.

Keywords: Cancer-associated fibroblast; Desmoplasia; Extracellular matrix; Inflammation; Lymphatic endothelial cell; Mesenchymal stem cell; Tumor microenvironment; Tumor-associated macrophage.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare no conflict of interests for this article.

Figures

Figure 1

Figure 1

Soluble factors derived from reactive stromal cells, along with tumor-associated extracellular matrix, sustain cholangiocarcinoma cell malignancy. CCA cells shape the surrounding microenvironment to meet their highly demanding needs, thus providing CAFs and TAMs with the ability to secrete a broad range of cyto/chemokines, growth factors, morphogens and proteinases, which boost cancer cell proliferation, survival and invasiveness. In this model, CAFs are recruited by PDGF-DD released by CCA cells. In addition, TGF-β1, also derived by CCA cells, stimulates CAFs to produce the EGFR ligand, HB-EGF, which triggers the acquisition of malignant behaviors (i.e., EMT-like changes) by cancer cells. CAF-derived tumor-promoting molecules also include IL-1β, SDF-1 and PDGF-BB. Moreover, PDGF-DD induces CAFs to acquire pro-lymphangiogenic functions (exerted by VEGF-A and VEGF-C). On the other hand, TAMs, displaying a predominant M2 phenotype, also support tumor survival and invasiveness by secreting several soluble factors, including MMP-9, TNF-α, IL-6, YKL-40 and Wnt3. Of note, the CCA stem-like compartment molds a specific subset of TAMs (through secretion of IL-13, IL-34 and osteoactivin), displaying a mixed M1/M2 phenotype, to promote self-renewal and drug-resistance properties. In addition, non-structural proteins expressed by the abnormally remodeled ECM (tenascin, periostin, osteopontin) further enhance CCA aggressiveness. CAF: Cancer-associated fibroblast; CCA: Cholangiocarcinoma; CSC: Cancer stem cell; ECM: Extracellular matrix; LEC: Lymphatic endothelial cell; TAM: Tumor-associated macrophage; IL: Interleukin; TGF: Transforming growth factor; TNF: Tumor necrosis factor; PDGF: Platelet-derived growth factor; EGFR: Epidermal growth factor receptor; MMP-9: Matrix metalloproteinase 9.

References

    1. Gatto M, Bragazzi MC, Semeraro R, Napoli C, Gentile R, Torrice A, Gaudio E, Alvaro D. Cholangiocarcinoma: update and future perspectives. Dig Liver Dis. 2010;42:253–260. - PubMed
    1. Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, Rosenberg WM, Tait P, Taylor-Robinson SD, Thillainayagam AV, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657–1669. - PubMed
    1. Zabron A, Edwards RJ, Khan SA. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Dis Model Mech. 2013;6:281–292. - PMC - PubMed
    1. Al-Bahrani R, Abuetabh Y, Zeitouni N, Sergi C. Cholangiocarcinoma: risk factors, environmental influences and oncogenesis. Ann Clin Lab Sci. 2013;43:195–210. - PubMed
    1. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–1229. - PMC - PubMed

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