fig1

Figure 1. Tumor progression and collagen patterns in iCCA. (1) Intrahepatic bile duct is composed of polarized cholangiocytes residing on a basement membrane; (2) In the desmoplastic reaction, cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) are co-opted with iCCA cells by secreting a huge variety of soluble factors. Subsequently, the activity of CAFs leads to type I and type III collagen deposition in the interstitial matrix and to the thickening of the basement membrane by type IV collagen; (3) Neoplastic cell invasion is accomplished by basement membrane dismantling; fibrillar collagens acquire a TACS-1-like structure surrounding the tumor boundary; lymphatic endothelial cells (LECs) and vascular endothelial cells (VECs) populate the tumor reactive stroma; (4) Gradually, type III collagen fibers become aligned and organized tangentially to the tumor mass. Paracrine signals released by TAMs, CAFs and iCCA cells lead to predominant sprouting of lymphatic vessels over the blood vasculature; (5) To complete the invasion-metastasis cascade, the aligned type III collagen organizes perpendicularly to the tumor boundary and acts as a binary track for neoplastic cells to escape toward the neo-formed lymph vessels.