Tumor microenvironment and cancer therapy resistance

Highlights

• Cancer gains resistance via multiple mechanisms involving cell intrinsic and extrinsic factors, but the latter often remains overlooked.

• Increasing evidence suggests that the TME plays a critical role in multiple aspects of cancer progression particularly resistance.

• Treatment itself frequently activates the TME, and a remodeled TME can accelerate cancer cell repopulation and exacerbate disease conditions.

• This review provides a body of updated information and delivers a balanced account of newly emerging fields in cancer research.

• A significant guide is presented to advance basic, translational and clinical oncology in the current era of precision medicine.

Abstract

Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, however, acquired resistance has emerged as a daunting challenge to anticancer treatments including chemotherapy, radiation and targeted therapy, which abolishes the efficacy of otherwise successful regimens. Cancer cells gain resistance through a variety of mechanisms in both primary and metastatic sites, involving cell intrinsic and extrinsic factors, but the latter often remains overlooked. Mounting evidence suggests critical roles played by the tumor microenvironment (TME) in multiple aspects of cancer progression particularly therapeutic resistance. The TME decreases drug penetration, confers proliferative and antiapoptotic advantages to surviving cells, facilitates resistance without causing genetic mutations and epigenetic changes, collectively modifying disease modality and distorting clinical indices. Recent studies have set the baseline for future investigation on the intricate relationship between cancer resistance and the TME in pathological backgrounds. This review provides an updated outline of research advances in TME biology and highlights the prospect of targeting the TME as an essential strategy to overcome cancer resistance and improve therapeutic outcomes through precise intervention. In the long run, continued inputs into translational medicine remain highly desired to achieve durable responses in the current era of personalized clinical oncology.

Introduction

The steps of tumor development implicate co-evolution of malignant cells and benign constituents of the surrounding stroma, while dynamic interactions between pathologically altered parenchyma and stroma within the TME represents a critical paradigm now considered among the typical hallmarks of cancer [1]. Histologically the association of infiltrating leukocytes and tumorigenesis was first described by Rudolf Virchow in 1863 to propose the potential relevance of chronic inflammation to neoplastic events [2]. Subsequently in 1889, Stephen Paget contributed a “seed and soil” concept to delineate the distinct patterns of recurrent metastatic sites in human breast cancer, and to plausibly interpret the tropism of tumor metastases to specific organs [3]. To date, a plethora of studies have disclosed the unique aspects of the TME, with its mystical veil removed and diverse characteristics ascertained. It is increasingly evident that individual compartments of the TME do not stay as quiet bystanders, but significantly regulate tumor initiation, disease progression, metastatic development, and more importantly, therapeutic response. Among multiple TME-implicated activities, clinical response to therapies is the major factor that directly determines the long term fate of patients who undergo anticancer interventions. In this review, an updated picture of tumor–stroma interaction is depicted, with a particular emphasis on the capacity of the TME in modifying cancer sensitivity to therapeutic agents. An appropriate, thorough and in-depth understanding of the functional roles of TME in disease evolution is essential for rational design, reasonable innovation and successful translation of novel anticancer approaches to precise medicine with substantially improved clinical outcomes.