Interplay between Solid Tumors and Tumor Microenvironment

Abstract

Over the past few decades, basic studies aimed at curing patients with cancer have been constantly evolving. A myriad of mechanistic studies on physiological changes and related factors in tumor growth and metastasis have been reported. Recently, several studies have been considerate to how tumors adapt to unfavorable environments, such as glucose deprivation, oxidative stress, hypoxic conditions, and immune responses. Tumors attempt to adapt to unfavorable environments with genetic or non-genetic changes, the alteration of metabolic signals, or the reconfiguration of their environment through migration to other organs. One of the distinct features in solid tumors is heterogeneity because their environments vary due to the characteristics of colony growth. For this reason, researchers are paying attention to the communication between growing tumors and neighboring environments, including stromal cells, immune cells, fibroblasts, and secreted molecules, such as proteins and RNAs. During cancer survival and progression, tumor cells undergo phenotype and molecular changes collectively referred to as cellular plasticity, which result from microenvironment signals, genetics and epigenetic alterations thereby contributing to tumor heterogeneity and therapy response. In this review, we herein discuss the adaptation process of tumors to adverse environments via communication with neighboring cells for overcoming unfavorable growth conditions. Understanding the physiology of these tumors and their communication with the tumor environment can help to develop promising tumor treatment strategies.

Keywords: extracellular matrix; metastasis; stromal cell; tumor heterogeneity; tumor microenvironment.

Figure 1

Intra-tumor heterogeneity by extrinsic or intrinsic factors. The modifications of cancer cells such as genetic, epigenetic alterations, and microenvironment perturbations. CSCs show an induced EMT system, which mostly exhibit an intermediate condition. This activity depends on both genetic mutations, epigenetic alterations, and transcriptional modification of cancer cells and signals provided by TME (CAFs or TAMs, immune cells, ECM, cytokines, secreted or growth factors). Thus, the intra-tumor heterogeneity might be play a potential role in the development of effective therapeutic approaches as drug resistance, tumor relapse and metastasis. CSCs, cancer stem-like cells; EMT, epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition; ECs, endothelial-like cells, CAFs, cancer-associated fibroblasts; TAMs, tumor-associated macrophages; ECM, extracellular matrix.

Figure 2

Stromal cells and the tumor microenvironment. CAA regulates EMT by secreting tumor necrosis factor (TNF)-α, IL-6, and FFA along with MMPs. Inflammatory cytokines are secreted by TAM and trigger chemokines. In CAF release, secreted factors and MMPs promote ECM remodeling. MSCs secrete exosomes along with mtDNAs and microRNAs (miRNAs). These molecules synergistically or individually promote tumor proliferation, drug resistance, and plasticity and affect tumor metastatic alteration. CAA, cancer-associated adipocytes; CAF, cancer-associated fibroblast; MSC, mesenchymal stem cell; TAM, tumor-associated macrophage.