Tackling the tumor microenvironment: what challenge does it pose to anticancer therapies?

Abstract

Cancer is a highly aggressive and devastating disease, and impediments to a cure arise not just from cancer itself. Targeted therapies are difficult to achieve since the majority of cancers are more intricate than ever imagined. Mainstream methodologies including chemotherapy and radiotherapy as routine clinical regimens frequently fail, eventually leading to pathologies that are refractory and incurable. One major cause is the gradual to rapid repopulation of surviving cancer cells during intervals of multiple-dose administration. Novel stress-responsive molecular pathways are increasingly unmasked and show promise as emerging targets for advanced strategies that aim at both de novo and acquired resistance. We highlight recent data reporting that treatments particularly those genotoxic can induce highly conserved damage responses in non-cancerous constituents of the tumor microenvironment (TMEN). Master regulators, including but not limited to NF-kB and C/EBP-β, are implicated and their signal cascades culminate in a robust, chronic and genome-wide secretory program, forming an activated TMEN that releases a myriad of soluble factors. The damage-elicited but essentially off target and cell non-autonomous secretory phenotype of host stroma causes adverse consequences, among which is acquired resistance of cancer cells. Harnessing signals arising from the TMEN, a pathophysiological niche frequently damaged by medical interventions, has the potential to promote overall efficacy and improve clinical outcomes provided that appropriate actions are ingeniously integrated into contemporary therapies. Thereby, anticancer regimens should be well tuned to establish an innovative clinical avenue, and such advancement will allow future oncological treatments to be more specific, accurate, thorough and personalized.

Figure 1

Schematic paradigm of resistance mechanisms in cancer treatment. Mechanisms underlying cancer therapy failure and treatment resistance are summarized. Factors implicated in either pharmacokinetic, cancer cell specific, or tumor microenvironmental categories have functional roles in treatment-induced responses. Changes in intracellular active drug concentrations, drug-target interactions, target-mediated cell damage, damage-induced cell death machineries or the signals from extracellular environments are actively at play under in vivo conditions. In contrast to other factors, the tumor microenvironment contains diverse stromal cell types (fibroblasts, smooth muscle cells, immune cells, endothelial cells, neuroendocrine cells, adipocytes, and pericytes) and comprises a large body of cytokines, chemokines, growth factors, proteinases, and hormones, most of which are signaling ligands, can impact pathophysiological responses to anticancer agents. Thus, the central determinants of therapeutic outcome may be highly dependent upon paracrine survival or stress signals. It is well documented that gene function and relevance varies remarkably when compared in vivo and in vitro, and studying the effect of defined genetic alterations on therapeutic response in either native or damaged tumor microenvironment is critical for effective drug development, personalized anticancer regimes, and optimal design of combination therapies. Colored text boxes: pink, pathways of drug actions; red, processes occurring in cancer cells during disease progression; yellow, signals generated by the tumor microenvironment. SC, subcutaneous injection; IP, intraperitoneal injection; IV, intravenous injection; ECM, extracellular matrix; TS, tumor suppressor

Figure 2

Therapy-induced DDR activation triggers the DDSP program and exerts a profound impact to cancer phenotypes. Upon therapeutic genotoxicity that mainly targets cancer cells, which are in active phases of turnaround and proliferation, cells within the TMEN have several responses. At minor damage, such as low doses of irradiation (0.5 Gy), DDR foci disappear within hours after complete DNA damage repair. In contrast, at higher doses (≥5 Gy), most damage foci in stromal cells persist for longer period, and cells enter senescence. Concurrently, majority of cancer cells are sensitized to such severe damage and directly go to apoptosis, while those with DDR-deficiency circumvent apoptosis and survive through treatment. High dosage of DNA damage usually triggers a persistent DDR engaging ATM, CHK2, and NBS1 which activates the cell cycle effectors p53/p16/RB, and leads to continuous and robust secretion of a large spectrum of proteins, dictated by a program coined as DDSP. A few secreted factors function in a cell-autonomous manner, such as IGFBP-7, IL-6, PAI-1, reinforcing senescence through a positive feedback loop that sustains the DDR. Several inflammatory cytokines (for example, CSF-1, MCP-1, CXCL-1, and IL-15), act in a cell non-autonomous way, and potentiate tumor regression by inducing the innate immune response that promotes tumor clearance. However, most components of the secretory phenotype promote cancer progression by enhancing survival, migration, invasiveness, and angiogenesis, accelerating cell repopulation, altering epithelial differentiation and causing epithelial-mesenchymal transition (EMT, e.g. IL-6, IL-8 and recently reported WNT16B and SPINK1). An advanced cancer phenotype, therapy resistance, hereby forms and once activated by such a program, cancer cells are more malignant and refractory to subsequent cycles of therapies. Colored cells: cyan, fibroblasts; green, smooth muscle cells; orange, benign epithelial cells; red, neoplastic epithelial cells; magenta, apoptotic cells; cross-shaped, cells undergoing transient DDR and in acute repair phase; star-shaped, cells that are permanently damaged, become senescent, and exhibit DDSP hallmarks

Figure 3

Potential effects of repopulation on total cell number between therapeutic cycles and a proposed clinical solution to circumvent pathological consequences. (A) Although a large portion of cancer cells is killed after each dose of administration, such as those given at 3-week intervals of radiation or chemotherapies, surviving cells can repopulate within a TMEN during the overall treatment period. Here, a constant rate of repopulation between doses is assumed, characterized by a doubling time of either 10 days (solid lines, red) or 2 months (dashed lines, blue). (B) Accelerating repopulation of surviving cancer cells frequently occurs between consecutive cycles, characterized by the indicated doubling times (blue line, cell number reduction phase; red line, increase phase). Such tendency can lead to cancer remission and regrowth, a phenomenon commonly observed in clinical practice, without any change in the cell intrinsic sensitivity to treatments. (C) Novel and innovative regimens integrating therapies that effectively target the DDSP phenotype of damaged TMEN (green arrows) have the advantage to curtail the potential of cancer cell repopulation. Ideally this should be applied consistently between successive courses to achieve optimal outcome in medical oncology