Tumor and its microenvironment: A synergistic interplay

Abstract

The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Recently, it was reported that targeting stromal events could improve efficacies of current therapeutics and prevent metastatic spreading. Tumor microenvironment is a “complex network” of different cell types, soluble factors, signaling molecules and extracellular matrix components, which orchestrate the fate of tumor progression. As by definition, cancer stem cells (CSCs) are proposed to be the unique cell type able to maintain tumor mass and survive outside the primary tumor at metastatic sites. Being exposed to environmental stressors, including reactive oxygen species (ROS), CSCs have developed a GSH-dependent antioxidant system to improve ROS defense capability and acquire a malignant phenotype. Nevertheless, tumor progression is dependent on extracellular matrix remodeling, fibroblasts and macrophages activation in response to oxidative stress, as well as epithelial mesenchymal transition (EMT)-inducing signals and endothelial and perivascular cells recruitment. Besides providing a survival advantage by inducing de novo angiogenesis, tumor-associated vessels contribute to successful dissemination by facilitating tumor cells entry into the circulatory system and driving the formation of pre-metastatic niche. In this review, we focus on the synergistic effect of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs) in the successful outgrowth of metastasis, integrating therefore many of the emerging models and theories in the field.

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and one of the major causes of death worldwide [1]. The prevention and the early diagnosis are surely the most important approaches for reducing the burden of CRC, given the symptoms of early disease occur just in 5% of cases. A significant portion of patients who receive surgery and adjuvant therapy still develop recurrences and metastasis and this phenomenon seems to be driven in some cell subsets by the acquisition of resistance to conventional therapy, such as chemo- and radio-therapy [2].

Growing evidence indicates that a cellular subpopulation with stem cell like features, commonly referred to as cancer stem cells (CSCs), is critical for tumor generation and maintenance.

A recent study showed that within the tumor population it is possible to identify a heterogeneous population of cells with different biological roles [3]. Recent advances in stem cell biology are revealing that this cellular fraction shares many properties with normal adult stem cells, including dormancy (quiescence), active DNA repair machinery, the expression of several ABC drugs transporters and an intrinsic resistance to apoptosis [4]. As their normal counterpart, the colon CSCs reside in a specialized microarchitectonic structures or niches that respond to both local and systemic conditions providing also protection against conventional therapies [5].

Moreover, microenvironmental stimuli, such as those involved in the epithelial-mesenchymal transition (EMT) and hypoxia, indirectly contribute to chemoresistance by inducing in cancer cells a stem like-phenotype. Understanding the driving force of tumor progression and the relationship between cancer cells and microenvironment could be fundamental in developing innovative therapeutic strategies for a better and definitive response on patient treatments.