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Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.

Pietras K, Pahler J, Bergers G, Hanahan D - PLoS Med. (2008)

Bottom Line: Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts.Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects.Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Diabetes Center and Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States ofAmerica. kristian.pietras@licr.ki.se

ABSTRACT

Background: Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.

Methods and findings: We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.

Conclusions: This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.

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Schematic Model of the Angiogenic Circuitry Operative during Malignant Progression in the Cervical Transformation Zone of HPV/E2 MiceThe transformed epithelial cells (purple) secrete VEGF, which becomes sequestered in the matrix until released by the action of MMP-9, produced by infiltrating macrophages (blue); the bioavailable VEGF then acts directly on endothelial cells (red) to stimulate angiogenesis. PDGF ligands are predominantly produced by the squamous epithelium and stimulate production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (brown) that express PDGF-receptors. FGF-2 stimulates angiogenesis by direct action on endothelial cells, and PDGF further promotes the angiogenic process by inducing pericyte (green) recruitment and association with newly formed blood vessels. FGF-7 may signal to the cervical carcinoma cells. Imatinib acts by inhibiting PDGF ligand-dependent PDGF receptor signaling (solid red lines), thereby repressing the production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (dotted red lines) and additionally reducing the pericyte coverage on tumor blood vessels. The clinically approved bisphosphonate zoledronate (zoledronic acid, Zometa, ZA) has been shown to suppress the expression of MMP-9 by macrophages (dotted red line), as well as to directly inhibit the proteolytic action of MMP-9 (solid red line).
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pmed-0050019-g007: Schematic Model of the Angiogenic Circuitry Operative during Malignant Progression in the Cervical Transformation Zone of HPV/E2 MiceThe transformed epithelial cells (purple) secrete VEGF, which becomes sequestered in the matrix until released by the action of MMP-9, produced by infiltrating macrophages (blue); the bioavailable VEGF then acts directly on endothelial cells (red) to stimulate angiogenesis. PDGF ligands are predominantly produced by the squamous epithelium and stimulate production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (brown) that express PDGF-receptors. FGF-2 stimulates angiogenesis by direct action on endothelial cells, and PDGF further promotes the angiogenic process by inducing pericyte (green) recruitment and association with newly formed blood vessels. FGF-7 may signal to the cervical carcinoma cells. Imatinib acts by inhibiting PDGF ligand-dependent PDGF receptor signaling (solid red lines), thereby repressing the production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (dotted red lines) and additionally reducing the pericyte coverage on tumor blood vessels. The clinically approved bisphosphonate zoledronate (zoledronic acid, Zometa, ZA) has been shown to suppress the expression of MMP-9 by macrophages (dotted red line), as well as to directly inhibit the proteolytic action of MMP-9 (solid red line).

Mentions: PDGF ligands are expressed in a variety of tumor types, as well as by epithelial cells during embryogenesis [13,14,50]. Our study employing the PDGF receptor inhibitor imatinib indicates that PDGF plays a dual role in the angiogenic phenotype of cervical SCC. A model for the angiogenic regulatory circuits contributing to neoplastic progression and tumor growth in the cervix of HPV/E2 mice, as elucidated by our studies (this work, and [24]), is shown in Figure 7. Consistent with previous studies in other tumor types [35,51,52], the data suggest that PDGF helps maintain pericyte support of the tumor vasculature. In addition, we have identified PDGF receptor signaling in CAFs as a mediator of the angiogenic response in tumors, by virtue of up-regulating expression of the proangiogenic factor FGF-2. We infer that both cellular targets, CAFs and pericytes, are contributing to the angiogenic phenotype and to its impairment by imatinib. In a model of islet cell carcinogenesis, imatinib was not antiangiogenic when used as monotherapy; rather it destabilized pericyte association and rendered coadministered endothelial cell inhibitors more effective in vessels lacking pericyte coverage [35–37]. In notable contrast, imatinib is directly antiangiogenic in the cervix as monotherapy, a result we have functionally attributed to FGF signaling from PDGFR-expressing CAFs (which are rare in the islet carcinoma model). Additionally, PDGF signaling elevates expression of FGF-7, which we infer may directly stimulate the cervical cancer cells, a possibility that deserves future investigation. Our findings are in agreement with earlier studies demonstrating production of both FGF-2 and FGF-7 by CAFs in response to PDGF [6]. We do not exclude the possibility that there will prove to be additional PDGF- and/or imatinib-regulated cross-talk between CAFs, carcinoma cells, and the other cell types constituting the tumor microenvironment, potentially embellishing the critical pathway we have elucidated.


Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.

Pietras K, Pahler J, Bergers G, Hanahan D - PLoS Med. (2008)

Schematic Model of the Angiogenic Circuitry Operative during Malignant Progression in the Cervical Transformation Zone of HPV/E2 MiceThe transformed epithelial cells (purple) secrete VEGF, which becomes sequestered in the matrix until released by the action of MMP-9, produced by infiltrating macrophages (blue); the bioavailable VEGF then acts directly on endothelial cells (red) to stimulate angiogenesis. PDGF ligands are predominantly produced by the squamous epithelium and stimulate production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (brown) that express PDGF-receptors. FGF-2 stimulates angiogenesis by direct action on endothelial cells, and PDGF further promotes the angiogenic process by inducing pericyte (green) recruitment and association with newly formed blood vessels. FGF-7 may signal to the cervical carcinoma cells. Imatinib acts by inhibiting PDGF ligand-dependent PDGF receptor signaling (solid red lines), thereby repressing the production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (dotted red lines) and additionally reducing the pericyte coverage on tumor blood vessels. The clinically approved bisphosphonate zoledronate (zoledronic acid, Zometa, ZA) has been shown to suppress the expression of MMP-9 by macrophages (dotted red line), as well as to directly inhibit the proteolytic action of MMP-9 (solid red line).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2214790&req=5

pmed-0050019-g007: Schematic Model of the Angiogenic Circuitry Operative during Malignant Progression in the Cervical Transformation Zone of HPV/E2 MiceThe transformed epithelial cells (purple) secrete VEGF, which becomes sequestered in the matrix until released by the action of MMP-9, produced by infiltrating macrophages (blue); the bioavailable VEGF then acts directly on endothelial cells (red) to stimulate angiogenesis. PDGF ligands are predominantly produced by the squamous epithelium and stimulate production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (brown) that express PDGF-receptors. FGF-2 stimulates angiogenesis by direct action on endothelial cells, and PDGF further promotes the angiogenic process by inducing pericyte (green) recruitment and association with newly formed blood vessels. FGF-7 may signal to the cervical carcinoma cells. Imatinib acts by inhibiting PDGF ligand-dependent PDGF receptor signaling (solid red lines), thereby repressing the production of FGF-2 and FGF-7 by carcinoma-associated fibroblasts (dotted red lines) and additionally reducing the pericyte coverage on tumor blood vessels. The clinically approved bisphosphonate zoledronate (zoledronic acid, Zometa, ZA) has been shown to suppress the expression of MMP-9 by macrophages (dotted red line), as well as to directly inhibit the proteolytic action of MMP-9 (solid red line).
Mentions: PDGF ligands are expressed in a variety of tumor types, as well as by epithelial cells during embryogenesis [13,14,50]. Our study employing the PDGF receptor inhibitor imatinib indicates that PDGF plays a dual role in the angiogenic phenotype of cervical SCC. A model for the angiogenic regulatory circuits contributing to neoplastic progression and tumor growth in the cervix of HPV/E2 mice, as elucidated by our studies (this work, and [24]), is shown in Figure 7. Consistent with previous studies in other tumor types [35,51,52], the data suggest that PDGF helps maintain pericyte support of the tumor vasculature. In addition, we have identified PDGF receptor signaling in CAFs as a mediator of the angiogenic response in tumors, by virtue of up-regulating expression of the proangiogenic factor FGF-2. We infer that both cellular targets, CAFs and pericytes, are contributing to the angiogenic phenotype and to its impairment by imatinib. In a model of islet cell carcinogenesis, imatinib was not antiangiogenic when used as monotherapy; rather it destabilized pericyte association and rendered coadministered endothelial cell inhibitors more effective in vessels lacking pericyte coverage [35–37]. In notable contrast, imatinib is directly antiangiogenic in the cervix as monotherapy, a result we have functionally attributed to FGF signaling from PDGFR-expressing CAFs (which are rare in the islet carcinoma model). Additionally, PDGF signaling elevates expression of FGF-7, which we infer may directly stimulate the cervical cancer cells, a possibility that deserves future investigation. Our findings are in agreement with earlier studies demonstrating production of both FGF-2 and FGF-7 by CAFs in response to PDGF [6]. We do not exclude the possibility that there will prove to be additional PDGF- and/or imatinib-regulated cross-talk between CAFs, carcinoma cells, and the other cell types constituting the tumor microenvironment, potentially embellishing the critical pathway we have elucidated.

Bottom Line: Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts.Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects.Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Diabetes Center and Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States ofAmerica. kristian.pietras@licr.ki.se

ABSTRACT

Background: Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.

Methods and findings: We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.

Conclusions: This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.

Show MeSH
Related in: MedlinePlus