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Hsp90 as a gatekeeper of tumor angiogenesis: clinical promise and potential pitfalls.

Bohonowych JE, Gopal U, Isaacs JS - J Oncol (2010)

Bottom Line: Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome.Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90) provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents.This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Molecular Pharmacology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.

ABSTRACT
Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome. Although antiangiogenic treatments appear promising, intrinsic and acquired tumor resistance contributes to treatment failure. Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90) provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents. This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways. The four main topics addressed include (1) Hsp90-mediated regulation of HIF/VEGF signaling, (2) chaperone-dependent regulation of HIF-independent VEGF-mediated angiogenesis, (3) Hsp90-dependent targeting of key proangiogenic receptor tyrosine kinases and modulation of drug resistance, and (4) consideration of factors such as tumor microenvironment that pose several challenges for the clinical efficacy of anti-angiogenic therapy and Hsp90-targeted strategies.

No MeSH data available.


Related in: MedlinePlus

Potential for Hsp90 intervention strategies in curtailing angiogenic processes. Tumor stromal cells, such as cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), communicate with tumor cells via their secretion of cytokines and thus contribute to the angiogenic switch (1). Cytokines from recruited BMDC progenitors contribute to this milieu to further stimulate tumor vascularization (1). Hsp90 inhibition may prevent HIF-driven cytokine release from tumor and stromal cells (i.e., SDF-1, VEGF, HGF, etc.), as well as HIF-mediated CXCR4+ expression in BMDCs, with the potential effect of curtailing recruitment of CXCR4+ progenitors to the tumor. Hsp90 inhibition also attenuates cytokine signaling via RTK inhibition (i.e., VEGFR, PDGFR), which may collectively prevent or delay the angiogenic switch. Therapeutic approaches utilizing radiotherapy (RT), tyrosine kinase inhibitors (TKIs), or Hsp90-targeted agents suppress tumor vascularization and growth (2). This initial reduction in vascularity may promote tumor hypoxia (3), subsequent HIF activation, and SDF-1 secretion, the latter of which may further stimulate BMDC recruitment (4). Hsp90 inhibitors are similarly predicted to suppress BMDC recruitment and HIF-driven cytokine secretion as in (1). Alternatively, when challenged with reduced HIF expression and decreased BMDC recruitment, tumor cells may coopt the vasculature of normal tissue (5). In this scenario, Hsp90 suppression is predicted to reduce the efficiency of EC-derived factors that support this process. The overall efficacy of Hsp90 inhibition upon tumor vascularization will depend upon the balance of Hsp90-dependent and Hsp90-independent signaling effectors driving the angiogenic process.
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Related In: Results  -  Collection


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fig2: Potential for Hsp90 intervention strategies in curtailing angiogenic processes. Tumor stromal cells, such as cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), communicate with tumor cells via their secretion of cytokines and thus contribute to the angiogenic switch (1). Cytokines from recruited BMDC progenitors contribute to this milieu to further stimulate tumor vascularization (1). Hsp90 inhibition may prevent HIF-driven cytokine release from tumor and stromal cells (i.e., SDF-1, VEGF, HGF, etc.), as well as HIF-mediated CXCR4+ expression in BMDCs, with the potential effect of curtailing recruitment of CXCR4+ progenitors to the tumor. Hsp90 inhibition also attenuates cytokine signaling via RTK inhibition (i.e., VEGFR, PDGFR), which may collectively prevent or delay the angiogenic switch. Therapeutic approaches utilizing radiotherapy (RT), tyrosine kinase inhibitors (TKIs), or Hsp90-targeted agents suppress tumor vascularization and growth (2). This initial reduction in vascularity may promote tumor hypoxia (3), subsequent HIF activation, and SDF-1 secretion, the latter of which may further stimulate BMDC recruitment (4). Hsp90 inhibitors are similarly predicted to suppress BMDC recruitment and HIF-driven cytokine secretion as in (1). Alternatively, when challenged with reduced HIF expression and decreased BMDC recruitment, tumor cells may coopt the vasculature of normal tissue (5). In this scenario, Hsp90 suppression is predicted to reduce the efficiency of EC-derived factors that support this process. The overall efficacy of Hsp90 inhibition upon tumor vascularization will depend upon the balance of Hsp90-dependent and Hsp90-independent signaling effectors driving the angiogenic process.

Mentions: Another factor in the disconnect between preclinical results and efficacy in patients is likely attributed to the influence of the tumor-adjacent stromal tissue. The tumor stroma, which influences the microenvironment surrounding the neoplastic lesion, is a driving force of both tumor growth and vascularization. This heterogenous stroma is comprised of a variety of cell types, including fibroblasts/myofibroblasts, smooth muscle cells and endothelial cells, immune cells, and bone marrow progenitor cells (Figure 2) [150], all of which collaborate to spur tumor growth. Clinically, an abundant fraction of the tumor reactive stroma is composed of cancer-associated fibroblasts (CAFs), or myofibroblasts, whose presence is recognized as a risk factor for neoplastic transformation. This tumor supporting function is due to their ability to upregulate ECM proteins and secrete growth factors and cytokines, (i.e., fibroblast growth factor (FGF), connective tissue growth factor (CTGF), stromal-derived factor (SDF-1) and VEGF), thereby creating conditions that constitute an optimal milieu for tumor development [151, 152]. CAFs robustly stimulate tumor angiogenesis and cancer progression in a number of xenograft models [153–157]. Myofibroblasts are also a component of nontumorigenic fibrotic tissue, such as in gastric, pancreatic, and hepatic stellate cells, which similarly secrete angiogenic cytokines and support paracrine signaling in adjacent epithelial cells [158]. Hypoxic signaling further drives fibrogenesis [159], and the hypoxia-mediated upregulation of VEGF and angiogenic cytokines from stellate cells perpetuates the fibrotic and hypoxic cycle [158, 160].


Hsp90 as a gatekeeper of tumor angiogenesis: clinical promise and potential pitfalls.

Bohonowych JE, Gopal U, Isaacs JS - J Oncol (2010)

Potential for Hsp90 intervention strategies in curtailing angiogenic processes. Tumor stromal cells, such as cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), communicate with tumor cells via their secretion of cytokines and thus contribute to the angiogenic switch (1). Cytokines from recruited BMDC progenitors contribute to this milieu to further stimulate tumor vascularization (1). Hsp90 inhibition may prevent HIF-driven cytokine release from tumor and stromal cells (i.e., SDF-1, VEGF, HGF, etc.), as well as HIF-mediated CXCR4+ expression in BMDCs, with the potential effect of curtailing recruitment of CXCR4+ progenitors to the tumor. Hsp90 inhibition also attenuates cytokine signaling via RTK inhibition (i.e., VEGFR, PDGFR), which may collectively prevent or delay the angiogenic switch. Therapeutic approaches utilizing radiotherapy (RT), tyrosine kinase inhibitors (TKIs), or Hsp90-targeted agents suppress tumor vascularization and growth (2). This initial reduction in vascularity may promote tumor hypoxia (3), subsequent HIF activation, and SDF-1 secretion, the latter of which may further stimulate BMDC recruitment (4). Hsp90 inhibitors are similarly predicted to suppress BMDC recruitment and HIF-driven cytokine secretion as in (1). Alternatively, when challenged with reduced HIF expression and decreased BMDC recruitment, tumor cells may coopt the vasculature of normal tissue (5). In this scenario, Hsp90 suppression is predicted to reduce the efficiency of EC-derived factors that support this process. The overall efficacy of Hsp90 inhibition upon tumor vascularization will depend upon the balance of Hsp90-dependent and Hsp90-independent signaling effectors driving the angiogenic process.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902748&req=5

fig2: Potential for Hsp90 intervention strategies in curtailing angiogenic processes. Tumor stromal cells, such as cancer-associated fibroblasts (CAFs) and endothelial cells (ECs), communicate with tumor cells via their secretion of cytokines and thus contribute to the angiogenic switch (1). Cytokines from recruited BMDC progenitors contribute to this milieu to further stimulate tumor vascularization (1). Hsp90 inhibition may prevent HIF-driven cytokine release from tumor and stromal cells (i.e., SDF-1, VEGF, HGF, etc.), as well as HIF-mediated CXCR4+ expression in BMDCs, with the potential effect of curtailing recruitment of CXCR4+ progenitors to the tumor. Hsp90 inhibition also attenuates cytokine signaling via RTK inhibition (i.e., VEGFR, PDGFR), which may collectively prevent or delay the angiogenic switch. Therapeutic approaches utilizing radiotherapy (RT), tyrosine kinase inhibitors (TKIs), or Hsp90-targeted agents suppress tumor vascularization and growth (2). This initial reduction in vascularity may promote tumor hypoxia (3), subsequent HIF activation, and SDF-1 secretion, the latter of which may further stimulate BMDC recruitment (4). Hsp90 inhibitors are similarly predicted to suppress BMDC recruitment and HIF-driven cytokine secretion as in (1). Alternatively, when challenged with reduced HIF expression and decreased BMDC recruitment, tumor cells may coopt the vasculature of normal tissue (5). In this scenario, Hsp90 suppression is predicted to reduce the efficiency of EC-derived factors that support this process. The overall efficacy of Hsp90 inhibition upon tumor vascularization will depend upon the balance of Hsp90-dependent and Hsp90-independent signaling effectors driving the angiogenic process.
Mentions: Another factor in the disconnect between preclinical results and efficacy in patients is likely attributed to the influence of the tumor-adjacent stromal tissue. The tumor stroma, which influences the microenvironment surrounding the neoplastic lesion, is a driving force of both tumor growth and vascularization. This heterogenous stroma is comprised of a variety of cell types, including fibroblasts/myofibroblasts, smooth muscle cells and endothelial cells, immune cells, and bone marrow progenitor cells (Figure 2) [150], all of which collaborate to spur tumor growth. Clinically, an abundant fraction of the tumor reactive stroma is composed of cancer-associated fibroblasts (CAFs), or myofibroblasts, whose presence is recognized as a risk factor for neoplastic transformation. This tumor supporting function is due to their ability to upregulate ECM proteins and secrete growth factors and cytokines, (i.e., fibroblast growth factor (FGF), connective tissue growth factor (CTGF), stromal-derived factor (SDF-1) and VEGF), thereby creating conditions that constitute an optimal milieu for tumor development [151, 152]. CAFs robustly stimulate tumor angiogenesis and cancer progression in a number of xenograft models [153–157]. Myofibroblasts are also a component of nontumorigenic fibrotic tissue, such as in gastric, pancreatic, and hepatic stellate cells, which similarly secrete angiogenic cytokines and support paracrine signaling in adjacent epithelial cells [158]. Hypoxic signaling further drives fibrogenesis [159], and the hypoxia-mediated upregulation of VEGF and angiogenic cytokines from stellate cells perpetuates the fibrotic and hypoxic cycle [158, 160].

Bottom Line: Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome.Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90) provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents.This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Molecular Pharmacology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.

ABSTRACT
Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome. Although antiangiogenic treatments appear promising, intrinsic and acquired tumor resistance contributes to treatment failure. Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90) provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents. This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways. The four main topics addressed include (1) Hsp90-mediated regulation of HIF/VEGF signaling, (2) chaperone-dependent regulation of HIF-independent VEGF-mediated angiogenesis, (3) Hsp90-dependent targeting of key proangiogenic receptor tyrosine kinases and modulation of drug resistance, and (4) consideration of factors such as tumor microenvironment that pose several challenges for the clinical efficacy of anti-angiogenic therapy and Hsp90-targeted strategies.

No MeSH data available.


Related in: MedlinePlus