Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Abstract

Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.

Keywords: adaptive resistance; cancer-associated fibroblasts; exosome; hypoxia; immunotherapy; therapeutic resistance; tumor microenvironment; vasculature system.

FIGURE 1

The main adaptive mechanisms driven by the TME for therapy resistance including CAFs, immune cells, vasculature system, ECM, exosomes, hypoxia, and acidity. CAFs, cancer-associated fibroblasts; ECM, extracellular matrix.

FIGURE 2

Immune system response for resistance in the TME. Scavenging of tumor cells by the immune system is mainly mediated by CTLs which can be inhibited by cytokines and chemokines secreted by several types of immune cells in the TME. There are also many molecules on the tumor surface which contribute to exhausting, or even eliminating, anti-tumor immune cells like CTLs. TME, tumor micro-environment; CTLs, cytotoxic T cells.

FIGURE 3

CAFs drive resistance-related paracrine pathways in the TME. CAFs provide an adaptive response for resistance by secreting chemokines, growth factors, metabolites, and exosomes, which activate various signaling pathways in cancer cells, including PI3K-Akt/MAPK, NF-κB, and STAT3. PI3K-Akt, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway; MAPK, mitogen-activated protein kinase pathway; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3.

FIGURE 4

Exosomes transfer therapy resistance between resistant cells and sensitive cells. Exosomes containing cargo, such as proteins and non-coding RNAs, that are related to pro-survival, anti-apoptosis, and drug-efflux factors, can promote the acquisition of resistance in tumor cells by modulating various processes, including the reduction of intracellular drug concentrations, induction of EMT, activation of anti-apoptotic pathways, alteration of critical survival signal transduction pathways, and modulation of the immune system.

FIGURE 5

The main signaling pathways responsible for therapeutic resistance mediated by the tumor environment. Tumor cells can adaptively inhibit oncogenic AKT, which induces the secretion of inflammatory molecules such as IL-6/8, and EVs to restrict damage during therapy. The ATM-TRAF6-TAK1 axis related with DNA damage may also be involved in resistance. Some metabolites, such as lactate, in the TME have been reported to activate the mTOR pathway through glutamine metabolic pathways, inducing resistance to VEGF inhibitors. In addition, the STAT3 pathway may also rapidly respond to cytokines, promoting the secretion of exosomes, by upregulating Rab and increasing anti-apoptotic signaling in the TME. IL-6 and exosomes derived from the stroma deliver Jag1, Notch ligand, and Notch3 activate the Notch pathway to trigger resistance.