Unveiling the role of tumor reactive stroma in cholangiocarcinoma: an opportunity for new therapeutic strategies

Abstract

Cholangiocarcinoma (CCA) is a very aggressive neoplasm, whose incidence has steadily increased in the last decade. Despite its growing epidemiological impact, therapeutic chances with a curative intent are still limited to surgical resection and, in highly selected cases, to liver transplantation. Unfortunately, in most cases at the time of diagnosis, CCA has already metastasized to regional lymph nodes, thereby reducing the opportunities for curative treatment. Mechanisms governing CCA invasiveness are unclear. A critical element of CCA is the abundant "tumor reactive stroma", which develops in close association with tumor growth. An abundant reactive stroma is present in a number of carcinomas characterized by strong invasiveness, namely gastric, colorectal and pancreatic cancers, as well as breast cancer. In tumor stroma, a variety of signals and mediators are reciprocally exchanged between stromal and cancer cells that, in turn acquire pro-invasive properties. These paracrine communications have started to be elucidated only recently, and may represent targets amenable of specific therapeutic intervention. In this review, we will highlight the cell types that compose the tumor reactive stroma in CCA and some of the molecular interactions possibly responsible for increased invasiveness of CCA. The possibility of dissecting, and likely exploiting, these interactions for potential new treatments will be also described.

Keywords: Cholangiocarcinoma; cancer-associated fibroblast; lymphangiogenesis; tumor reactive stroma; tumor-associated macrophage.

Figure 1

Cellular and molecular mechanisms regulating the generation of the tumor reactive stroma in CCA. Following neoplastic transformation, cholangiocytes start to secrete a wide range of cytokines, growth factors and enzymes, providing them with the ability to dismantle the basement membrane and to establish an intense cross-talk with different cell types. A range of paracrine signals released by neoplastic cholangiocytes orchestrate the recruitment of mesenchymal cells to the site of tumor growth: in particular, VEGF-A and PDGF-D stimulate the migration of resident fibroblasts, CCL2(MCP-1) dictate the monocyte homing from blood circulation, and VEGF-C/-D recruit lymphatic endothelial cells. In recruited cells, the tumor microenvironment further stimulates their transdifferentiation into CAF and TAM, leading to the deposition of ECM components and to lymphangiogenesis, critical mechanisms of CCA dissemination

Figure 2

Phenotyping the tumor reactive stroma in CCA. Immunohistochemistry of different markers to characterize cells and structural components of the tumor reactive stroma in CCA: CAF (α-SMA, A), ECM (Fibronectin, B), inflammatory cells (CD45, C), TAM (CD206, D, arrows), lymphatic endothelial cells (Podoplanin, E) and vascular endothelial cells (CD34, F). A stark unbalance between the lymphatic and the blood vascular bed is observed in CCA. Notably, lymphatic vessels lay in close vicinity to neoplastic bile ducts, strictly aligned along the ductal profile. Histological specimens were derived from surgical liver resection of patients with iCCA. Original magnification: 200×