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.

Tumor microenvironment and cancer therapy resistance

“…Cell culture assays and tumor xenograft models demonstrated the protective effect of stroma-derived WNT16B, indicating that WNT16B produced by the TME attenuates cancer cell apoptosis caused by genotoxicity, and confers tumor insensitivity to therapeutic agents through activation of a stroma-intense secretory phenotype. Phenotypes driven by the DDSP are distinct and the associated secretion is robust, with many extracellular proteins overexpressed by ten-fold or even higher (for instance, MMP1 by 76-fold and WNT16B by 34-fold, respectively), and the effects are supposed to be chronical as evidenced by effector secretion in TME niches of clinical specimens collected even months (or years) after radical surgery of cancer patients [6,73].…”

“…In breast cancer, malignant cell attachment to ECM alters their polarization and causes resistance to etoposide-induced apoptosis [31]. Specifically, cell adhesion-mediated drug resistance (CAM-DR) depends on association of integrin to ECM components including fibronectin, collagen and laminin [6]. Integrin-implicated cancer resistance is not limited to chemotherapies, but applies to radiation and targeted therapies by attenuating activities of receptor tyrosine kinases (RTKs) such as EGFR [32,33].…”

“…Despite considerable advancements in therapeutic concepts and techniques, disease relapse with limited response remains a major challenge and confers poor prognosis in clinical oncology. Cancer resistance involves intrinsic mechanisms that are determined by pre-existing genetic and/or epigenetic properties of malignant cells including enhanced drug efflux, blunted apoptotic signaling, increased metabolic activities, loss of specific oncogenes, gain of stem cell plasticity and strengthened DNA damage repair machinery, all fueled by mutation-selective pressure that engenders clonal expansion and creates tumor heterogeneity [5,6]. In contrast, extrinsic resistance of cancer cells driven by the TME represents a seemingly minor but essentially pivotal modality that substantially influences therapeutic efficacy.…”

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

“…The existence of CSCs within tumors, together with the active pathological role currently recognized for the tumor microenvironment that influences acquired resistance, immune evasion and metastization [20,21], further favors the search for a combination of repurposed drugs against the whole tumor system, likely acting on intracellular mechanisms that differ from those targeted by standard anticancer agents [22].…”

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

“…Fortunately, a handful of agents successfully acquired FDA approval for the systemic intervention of cancer patients while many others are in the industrial pipelines or clinical trials. As scientific acumen, an optimal therapeutic strategy is to consider the cancer a systemic disease at diagnosis and to pursue combinational therapy that incorporate cytotoxic agents and feasible cytostatic drugs either concurrently or sequentially, the latter actually more preferred [83]. Continued efforts in future will consolidate preclinical studies with novel therapeutics that deprive cancer of TME-conferred resistance, which is administered synergistically with cancer-targeting agents in pathological conditions that implicate a stress-responsive and functionally active TME.…”