New horizons in tumor microenvironment biology: challenges and opportunities

Abstract

The tumor microenvironment (TME) is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. An appropriate understanding of the TME promotes evaluation and selection of candidate agents to control malignancies at both the primary sites as well as the metastatic settings. This review presents a timely outline of research advances in TME biology and highlights the prospect of targeting the TME as a critical strategy to overcome acquired resistance, prevent metastasis, and improve therapeutic efficacy. As benign cells in TME niches actively modulate response of cancer cells to a broad range of standard chemotherapies and targeted agents, cancer-oriented therapeutics should be combined with TME-targeting treatments to achieve optimal clinical outcomes. Overall, a body of updated information is delivered to summarize recently emerging and rapidly progressing aspects of TME studies, and to provide a significant guideline for prospective development of personalized medicine, with the long term aim of providing a cure for cancer patients.

Figure 1

Cancer develops in a complex and dynamic TME, which exerts profound impacts to disease progression. Cancer cells are in close relationship with diverse non-cancer cell types within the TME, forming a functional nexus that facilitates tumor initiation, survival, and exacerbation. Cytotoxicity generated by treatments including chemotherapy, radiation, and targeted therapy eliminates many malignant cells within the cancer cell population; however, surviving cells are frequently retained in specific TME niches. Such protection minimizes the sensitivity to anti-cancer agents and generates resistant subclones through distinct mechanisms, prominently through acquired resistance conferred by a large body of soluble factors released from damaged or remodeled stroma. Alternatively, BMDCs, including MSCs and Tregs, mediate immunomodulation and prevent inflammation by restraining the activity of cytotoxic T cells, correlating with poor prognosis. Either acquired resistance or immunosurveillance evasion promotes cancer cell survival and subsequent expansion, allowing development of more advanced phenotypes, including tumor relapse, distant metastasis, and therapeutic failure, eventually causing high mortality in clinical settings. CAF, Carcinoma-associated fibroblast; MSC, Mesenchymal stem cell; BMDC, Bone marrow-derived cell; Treg cell, Regulatory T cell; EC, Endothelial cell; ECM, Extracellular matrix; TAM, Tumor-associated macrophage.

Figure 2

Illustrative models for the preclinical evaluation of novel anticancer regimes that incorporate TME-targeting agents. (A) Route 1 (singular), tumors develop in transgenic mice before the preclinical administration of chemotherapy or targeted therapy is applied as a singular agent. Dramatic cancer resistance is observed in such a therapeutic approach, with only limited efficacy available. (B) Route 2 (combinational), in contrast to route 1, an updated regime incorporating the novel agents (small molecule inhibitor or monoclonal antibodies) into the treatment program, which allows targeting both the tumor and TME. Significant disease regression follows after several cycles of the novel treatments, with much higher preclinical index achieved. (C) Route 3 (singular), tumors develop in the immunocompetent (wild type) mice xenografted with cancer cells and stromal cells from the same genetic and/or strain background as the host. Upon exposure to treatments as in Route A, a low outcome is observed. (D) Route 4 (combinational), tumors develop in the xenograft mice as in C, harboring implanted cancer and stromal components. Once receiving the same treatments as in Route B, animals present significantly improved therapeutic efficacy. (Note, in routes C and D, the preclinical paradigm in prospective trials exclude PDX, although it is a highly recommended model for many cancer studies).