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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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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
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Fig3: 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

Mentions: Upon chemotherapy tumor growth will follow a Gompertzian curve, and the rate of regrowth would be faster after shrinkage induced by treatment (Norton and Simon, 1986). In a model to mimic the responses of cancer cells during repopulation that occurs in courses of chemotherapy given at three-week intervals, it is reasonable to assume that the rate of repopulation remains constant but increases in the intervals between successive courses of treatment, whereas chemotherapy inhibits proliferation temporarily after treatment but triggers subsequent repopulation which accelerates between successive cycles of chemotherapy (Kim and Tannock, 2005). Increased cellular sensitivity to cytotoxic drugs generated by rapid proliferation might be countered by the tendency to select cells with acquired resistance conferred by enhanced secretion of DDSP factors from adjacent TMEN in the context of hypoxia. In clinical conditions, this problem may be technically solved by artful administration of anti-DDSP agents between cycles of therapy, a feasible and practical way to minimize the influence of cancer-promoting factors from DNA-damaged cells that develop a secretory phenotype (Fig. 3).Figure 3


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: 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
Mentions: Upon chemotherapy tumor growth will follow a Gompertzian curve, and the rate of regrowth would be faster after shrinkage induced by treatment (Norton and Simon, 1986). In a model to mimic the responses of cancer cells during repopulation that occurs in courses of chemotherapy given at three-week intervals, it is reasonable to assume that the rate of repopulation remains constant but increases in the intervals between successive courses of treatment, whereas chemotherapy inhibits proliferation temporarily after treatment but triggers subsequent repopulation which accelerates between successive cycles of chemotherapy (Kim and Tannock, 2005). Increased cellular sensitivity to cytotoxic drugs generated by rapid proliferation might be countered by the tendency to select cells with acquired resistance conferred by enhanced secretion of DDSP factors from adjacent TMEN in the context of hypoxia. In clinical conditions, this problem may be technically solved by artful administration of anti-DDSP agents between cycles of therapy, a feasible and practical way to minimize the influence of cancer-promoting factors from DNA-damaged cells that develop a secretory phenotype (Fig. 3).Figure 3

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