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.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…Indeed, a substantial proportion of cholangiocarcinomas are surrounded by a reactive tumour stroma, populated by host cells including cancer-associated fibroblasts, endothelial cells, and immune cells, including tumour-associated macrophages (TAMs) 153,154 . These stromal elements produce soluble factors including various interleukins, growth factors, and cytokines, which in turn can promote tumour-cell proliferation, survival, and invasiveness, and modulate anticancer immune responses.…”

The tumour microenvironment and immune milieu of cholangiocarcinoma

“…Tumour-associated macrophages (TAMs) are the most relevant infiltrating immune cell population within the tumour microenvironment. 56 High tissue macrophage density has been associated with poor prognosis of patients with CCA. 57 Furthermore, circulating CD14 + /CD16 + monocyte levels correlate with TAM infiltration and are associated with poor prognosis.…”

Liver Matrix in Benign and Malignant Biliary Tract Disease

“…69 Driven by the tumor epithelial counterpart, the surrounding stroma is gradually converted from the normal thin framework underlying the basal aspect of the ductal epithelial cell layers, into a thick and dense scaffolding whereby a crowd of multiple stromal cell types is recruited and activated (tumor reactive stroma). 70 , generating a vast array of cues that variably shape the tumor cell traits. 71 While it was first believed that the stromal reaction harbored tumor-promoting properties, recent data derived from both experimental models and clinical trials have called into questions this assumption.…”