The Tumor Microenvironment in Aggressive Gastro-Intestinal Cancers: Lymphatic Vessels, Macrophages and Fibroblasts

Abstract

Since the onset of cancer research, much of the focus has been on how normal cells acquire aberrant properties and evolve into cancer cells, eventually forming malignant tumors. Advancing knowledge has resulted in valuable current anti-cancer therapies. However, unfortunately they often remain incompletely effective. Therefore, these past decades cancer research has expanded its focus to other contributing factors involved in cancer progression. It is now widely accepted that the ‘normal’ tissues surrounding tumor cells exert a crucial influence on this evolution. This neighboring habitat of cancer cells is called the tumor microenvironment (TME), also referred to as the tumor stroma. Cancer cells hijack and corrupt these surrounding cells to forge a permissive and enabling environment for tumor progression. By continuous cross talk with their TME, cancer cells mold their surroundings to support tumor growth, local invasion and metastasis. Not surprisingly, the TME appears to greatly contribute to a tumor’s aggressive nature. Moreover, as a dynamic habitat, continuously changing during the course of cancer progression, the TME also plays a crucial part in therapy resistance. For instance by promoting tumor cell survival and chemotherapy-resistance as well as by influencing drug delivery and distribution. As such, tumor cell-TME interactions set the stage for tumor outgrowth and tumor recurrence after therapy. Therefore, a strong research focus on TME interactions influencing cancer progression, metastasis, therapy resistance, and the implications for possible future therapeutic strategies has emerged. This thesis focuses on the tumor microenvironment of specific cancers of the gastro-intestinal tract, namely colorectal cancer and cholangiocarcinoma, and the influence of TME-tumor cross talk on cancer progression and metastasis. Here, we explored the interactions of tumor cells with 3 neighboring cell types: lymphatic endothelial cells, macrophages and fibroblasts. In short, we explore whether the lymphatic system of the liver has preferential routes for lymphatic drainage to regional lymph nodes, develop a representative in vitro model for lymphatic vasculature and tumor co-culture using 3D microfluidic Organ-on-a-Chip technology, establish a liver tissue clearing technique capable of immunolabeling blood vasculature and tumor cells, study the effect of tumor-associated macrophages on tumor budding and local invasion, use cancer organoid technology to study important lymphatic pathway mediators VEGF-C and Neuropilin-2, the applicability of targeting cancer-associated fibroblasts in PET imaging of cholangiocarcinoma, as well as study the effect of liver surgery versus radiofrequency ablation on cytokine and chemokine expression in the tumor microenvironment.