Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness

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

Core tip: Cholangiocarcinoma (CCA) is a typically worrisome malignancy, whose incidence has been steadily increasing. In CCA, as cancerous lesions are emerging, the surrounding stroma gradually undergoes a pathological remodeling, eventually becoming a paramount determinant of tumor growth and dissemination. Indeed, the different cell types populating the tumor microenvironment, also referred to as tumor reactive stroma, enable CCA cells to develop an aggressive phenotype, due to the secretion of a multitude of soluble factors. Therefore, functional insights into the harmful relationship between cancer and reactive stromal cells are of utmost importance, in order to unveil novel molecular targets amenable of therapeutic intervention.