Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures

Abstract

Chemotherapy and targeted therapy have opened new avenues in clinical oncology. However, there is a lack of response in a substantial percentage of cancer patients and diseases frequently relapse in those who even initially respond. Resistance is, at present, the major barrier to conquering cancer, the most lethal age-related pathology. Identification of mechanisms underlying resistance and development of effective strategies to circumvent treatment pitfalls thereby improving clinical outcomes remain overarching tasks for scientists and clinicians. Growing bodies of data indicate that stromal cells within the genetically stable but metabolically dynamic tumor microenvironment confer acquired resistance against anticancer therapies. Further, treatment itself activates the microenvironment by damaging a large population of benign cells, which can drastically exacerbate disease conditions in a cell nonautonomous manner, and such off-target effects should be well taken into account when establishing future therapeutic rationale. In this review, we highlight relevant biological mechanisms through which the tumor microenvironment drives development of resistance. We discuss some unsolved issues related to the preclinical and clinical trial paradigms that need to be carefully devised, and provide implications for personalized medicine. In the long run, an insightful and accurate understanding of the intricate signaling networks of the tumor microenvironment in pathological settings will guide the design of new clinical interventions particularly combinatorial therapies, and it might help overcome, or at least prevent, the onset of acquired resistance.

Keywords: acquired resistance; cancer therapy; clinical intervention; translational medicine; tumor microenvironment.

Figure 1

A synoptic paradigm of cancer resistance mechanisms. Resistance to cancer therapies is a major problem facing current clinical oncology. The mechanisms of resistance to classical cytotoxic chemotherapeutics and to therapies designed for selective molecular targets share many features. Upon clinical administration, pharmacokinetic and cell intrinsic factors play important roles in supporting cancer survival, adaptation, and eventually relapse, all are essential steps of resistance phenotype development. However, in response to evolving pathological conditions, oncogenic signals from growing tumors, the tumor microenvironment continually changes over the course of cancer progression, underscoring the need to reconsider its influences as a dynamic process and how tumor drives the construction of its own niche. Bold arrows, pharmacokinetic steps; black text boxes, intrinsic processes occurring in cancer cells during disease progression; dashed and color arrows, factors derived from the neighboring tumor microenvironments that are often activated by various events.

Figure 2

Typical pathological components and signals of the tumor microenvironment. An assemblage of distinct cell types and structural scaffold constitutes most solid tumors such as prostate, lung, and breast cancers. Both the parenchyma and stroma of tumors contain multiple cell types and subtypes that collectively enable tumor growth and progression. Multiple stromal cell types create a succession of tumor microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues. The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the ECM, evolve during progression, thereby enabling primary, invasive, and then metastatic growth. A large array of soluble factors are generated and disseminated into the surrounding milieu, drastically promoting cancer cell survival and stimulate repopulation during the courses of chemotherapy and targeted therapy. Notably, the immune inflammatory cells present in the microenvironment also contribute to therapy resistance by secreting numerous growth factors, cytokines, chemokines that further exacerbate such pathological conditions. ECM, extracellular matrix; CAF, carcinoma-associated fibroblast; ROS, reactive oxygen species; RNS, reactive nitrogen species.

Figure 3

WNT16B is generated upon genotoxic damage to prostate fibroblasts and confers acquired resistance to prostate cancer cells. (A) Bioinformatics analysis of gene expression changes in prostate fibroblasts by microarray hybridization. The heatmap depicts the relative transcript abundance levels after exposure to hydrogen peroxide (H₂0₂), bleomycin (BLEO), or ionizing radiation (RAD), agents inducing typical DNA damages. (B) Heatmap and average fold-change measurements of genes annotated as extracellular or secreted factors. Note WNT16B is on the top list of upregulated genes. (C) A model for cell-nonautonomous therapy resistance effects originating in the TME upon genotoxic therapeutics. The initial round of therapy engages an apoptotic or senescence response in subsets of cancer cells and activates a DNA damage response (DDR) in DDR-competent benign cells (+DDR) comprising the TME. The DDR includes a spectrum of autocrine- and paracrine-acting proteins that are capable of reinforcing a senescent phenotype in benign cells and promoting cancer cell repopulation. Paracrine-acting secretory factors including WNT16B promote resistance to subsequent cycles of cytotoxic or targeted therapy. CEC, cancer epithelial cell; BEC, benign epithelial cell; FC, fibroblast cell; −DDR, DDR-incompetent benign cells. Color images adapted from Sun et al. with permission from Nature Medicine, copyright 2012.

Figure 4

Acquired resistance emerges during anticancer therapies and the long-term consequences include development of circulating tumor cells (CTCs), ectopic metastasis, tumor relapse, and treatment failure. The complex TME is not static, but dynamically responds to a variety of stimuli. Emerging data indicate that chemotherapies particularly genotoxic regimes activate highly conserved damage response programs in benign constituents of the TME. These damage signals, transmitted via master regulators such as NF-κB and C/EBPβ, culminate in a powerful and diverse secretory program DDSP, which generates an activated stroma. Downstream effectors of this program include IL-6, IL-8, WNT16B, SFRP2, SPINK1, and other factors that have been shown to promote adverse cancer phenotypes, among which enhanced resistance is a major and most challenging clinical bottleneck to provide effective cures. The pathological consequence includes initial emerging and subsequent development of CTCs, dissemination of CTCs to multiple distant sites, disease recurrence, and eventual treatment failure. Color image adapted from Kang and Pantel with permission from Cancer Cell, copyright 2013.