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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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Related in: MedlinePlus

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
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Fig2: 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

Mentions: Thus, as evidenced by multiple studies, DNA damage is able to force surviving cells to enter senescence and engage a fairly complicated network that mediates the development of a signal transduction cascade. Damaged cells thereby exert comprehensive impacts to surrounding tissues with the accompanying, inherent, and conserved phenotype-DDSP, which can be turned on after clinical administration of genotoxic therapies against the extremely lethal human pathology, cancer (Fig. 2).Figure 2


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: 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
Mentions: Thus, as evidenced by multiple studies, DNA damage is able to force surviving cells to enter senescence and engage a fairly complicated network that mediates the development of a signal transduction cascade. Damaged cells thereby exert comprehensive impacts to surrounding tissues with the accompanying, inherent, and conserved phenotype-DDSP, which can be turned on after clinical administration of genotoxic therapies against the extremely lethal human pathology, cancer (Fig. 2).Figure 2

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