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

Chen F, Qi X, Qian M, Dai Y, Sun Y - Protein Cell (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

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.

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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
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Fig1: 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

Mentions: Although the standard care for cancer patients is usually a combination of surgery and DNA damaging therapy for cytoreduction or cytostasis under pathological circumstances, drug sensitivity is compromised in almost all patients with metastatic diseases. Reasons for such “apparent drug resistance” can be classified into three categories: pharmacokinetic, cancer cell innate and microenvironmental. A basic model of the functional roles of these interactive mechanisms is illustrated in Fig. 1. At molecular levels, although resistance is usually a consequence of cancer cell intrinsic genetic changes including enhanced genomic instability and mutagenesis, epigenetic alterations, decreased oxidative stress, presence of multiple drug resistance (MDR) transporters and up-regulation of drug efflux pumps (Wang and Chen, 2013; Goruppi and Dotto, 2013), an emerging body of studies pinpoints that resistance to cancer therapies is also conferred by cell extrinsic factors such as cytokines, growth factors, proteases and other soluble ligands generated from the TMEN (Campisi, 2013). These factors play key roles in regulating tumor cell proliferation, survival and malignancy through the activation of diverse signaling pathways, including the Smad, PI3K, Jak/Stat, NF-κB, MAPK, CXCR2 and IL-1 network (Nguyen et al., 2009; Ohanna et al., 2011; Coppé et al., 2011).Figure 1


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

Chen F, Qi X, Qian M, Dai Y, Sun Y - Protein Cell (2014)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4225463&req=5

Fig1: 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
Mentions: Although the standard care for cancer patients is usually a combination of surgery and DNA damaging therapy for cytoreduction or cytostasis under pathological circumstances, drug sensitivity is compromised in almost all patients with metastatic diseases. Reasons for such “apparent drug resistance” can be classified into three categories: pharmacokinetic, cancer cell innate and microenvironmental. A basic model of the functional roles of these interactive mechanisms is illustrated in Fig. 1. At molecular levels, although resistance is usually a consequence of cancer cell intrinsic genetic changes including enhanced genomic instability and mutagenesis, epigenetic alterations, decreased oxidative stress, presence of multiple drug resistance (MDR) transporters and up-regulation of drug efflux pumps (Wang and Chen, 2013; Goruppi and Dotto, 2013), an emerging body of studies pinpoints that resistance to cancer therapies is also conferred by cell extrinsic factors such as cytokines, growth factors, proteases and other soluble ligands generated from the TMEN (Campisi, 2013). These factors play key roles in regulating tumor cell proliferation, survival and malignancy through the activation of diverse signaling pathways, including the Smad, PI3K, Jak/Stat, NF-κB, MAPK, CXCR2 and IL-1 network (Nguyen et al., 2009; Ohanna et al., 2011; Coppé et al., 2011).Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

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.

Show MeSH
Related in: MedlinePlus