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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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Effects of Treating HPV/E2 Mice with the PDGF Receptor Inhibitor Imatinib(A) Tumor volume of carcinomas in the uterine cervixes of cohorts of mice treated (or not) with imatinib for 4 wk in an intervention trial, ending at 6 mo of age. Mann-Whitney U test, U = 5, p < 0.05.(B and C) Incidence (χ2 test, χ2 = 5.1, p < 0.05) (B) and tumor volume (Mann-Whitney U test, U = 46, p < 0.05) (C) of invasive tumors in the uterine cervix following a 6-wk-long prevention trial ending at 5 mo of age. Mice without carcinomas had CIN2–3 lesions.(D and E) Analysis of the proliferative (Student t-test, t(CIN3) = 2.3, p < 0.05; t(SCC) = 3.6, p < 0.01) (D) and apoptotic index (Student t-test, t(CIN3) = 3.1, p < 0.01; t(SCC) = 3.6, p < 0.01) (E) of CIN and SCC lesions in the cervixes of HPV/E2 mice treated in the prevention trial with vehicle or imatinib. Error bars indicate the standard error of the mean.
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pmed-0050019-g002: Effects of Treating HPV/E2 Mice with the PDGF Receptor Inhibitor Imatinib(A) Tumor volume of carcinomas in the uterine cervixes of cohorts of mice treated (or not) with imatinib for 4 wk in an intervention trial, ending at 6 mo of age. Mann-Whitney U test, U = 5, p < 0.05.(B and C) Incidence (χ2 test, χ2 = 5.1, p < 0.05) (B) and tumor volume (Mann-Whitney U test, U = 46, p < 0.05) (C) of invasive tumors in the uterine cervix following a 6-wk-long prevention trial ending at 5 mo of age. Mice without carcinomas had CIN2–3 lesions.(D and E) Analysis of the proliferative (Student t-test, t(CIN3) = 2.3, p < 0.05; t(SCC) = 3.6, p < 0.01) (D) and apoptotic index (Student t-test, t(CIN3) = 3.1, p < 0.01; t(SCC) = 3.6, p < 0.01) (E) of CIN and SCC lesions in the cervixes of HPV/E2 mice treated in the prevention trial with vehicle or imatinib. Error bars indicate the standard error of the mean.

Mentions: Having documented the expression of PDGF ligands in the neoplastic epithelia and PDGF receptors in the stroma at all stages in cervical carcinogenesis, we sought to assess the functional significance and therapeutic potential of PDGF signaling by pharmacological inhibition at distinct stages of cervical carcinogenesis. We chose to disrupt PDGF receptor signaling with the kinase inhibitor imatinib (Gleevec) [38], which we and others have documented to be effective at inhibiting PDGF receptor in mice [39,40]. To establish the efficacy of imatinib treatment in the cervix, we immunoprecipitated PDGF receptor-α from cervical tissue lysates from HPV/E2 mice treated twice daily for 2 wk with imatinib. Western blotting for activated PDGF receptor-α revealed that the phosphotyrosine content of the receptor was reduced by 72% following treatment with imatinib (Figure S1). The first therapeutic trial was initiated at the age of 5 mo, when more than 80% of the mice display overt carcinoma lesions in the cervix [24]. The trial continued for 1 mo (an Intervention Trial). The median tumor volume at this temporally defined endpoint was decreased by 61% following imatinib treatment, demonstrating that this agent can impair the maintenance and growth of preexisting cervical tumors (Figure 2A; Mann-Whitney U test, U = 5, p < 0.05).


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)

Effects of Treating HPV/E2 Mice with the PDGF Receptor Inhibitor Imatinib(A) Tumor volume of carcinomas in the uterine cervixes of cohorts of mice treated (or not) with imatinib for 4 wk in an intervention trial, ending at 6 mo of age. Mann-Whitney U test, U = 5, p < 0.05.(B and C) Incidence (χ2 test, χ2 = 5.1, p < 0.05) (B) and tumor volume (Mann-Whitney U test, U = 46, p < 0.05) (C) of invasive tumors in the uterine cervix following a 6-wk-long prevention trial ending at 5 mo of age. Mice without carcinomas had CIN2–3 lesions.(D and E) Analysis of the proliferative (Student t-test, t(CIN3) = 2.3, p < 0.05; t(SCC) = 3.6, p < 0.01) (D) and apoptotic index (Student t-test, t(CIN3) = 3.1, p < 0.01; t(SCC) = 3.6, p < 0.01) (E) of CIN and SCC lesions in the cervixes of HPV/E2 mice treated in the prevention trial with vehicle or imatinib. Error bars indicate the standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2214790&req=5

pmed-0050019-g002: Effects of Treating HPV/E2 Mice with the PDGF Receptor Inhibitor Imatinib(A) Tumor volume of carcinomas in the uterine cervixes of cohorts of mice treated (or not) with imatinib for 4 wk in an intervention trial, ending at 6 mo of age. Mann-Whitney U test, U = 5, p < 0.05.(B and C) Incidence (χ2 test, χ2 = 5.1, p < 0.05) (B) and tumor volume (Mann-Whitney U test, U = 46, p < 0.05) (C) of invasive tumors in the uterine cervix following a 6-wk-long prevention trial ending at 5 mo of age. Mice without carcinomas had CIN2–3 lesions.(D and E) Analysis of the proliferative (Student t-test, t(CIN3) = 2.3, p < 0.05; t(SCC) = 3.6, p < 0.01) (D) and apoptotic index (Student t-test, t(CIN3) = 3.1, p < 0.01; t(SCC) = 3.6, p < 0.01) (E) of CIN and SCC lesions in the cervixes of HPV/E2 mice treated in the prevention trial with vehicle or imatinib. Error bars indicate the standard error of the mean.
Mentions: Having documented the expression of PDGF ligands in the neoplastic epithelia and PDGF receptors in the stroma at all stages in cervical carcinogenesis, we sought to assess the functional significance and therapeutic potential of PDGF signaling by pharmacological inhibition at distinct stages of cervical carcinogenesis. We chose to disrupt PDGF receptor signaling with the kinase inhibitor imatinib (Gleevec) [38], which we and others have documented to be effective at inhibiting PDGF receptor in mice [39,40]. To establish the efficacy of imatinib treatment in the cervix, we immunoprecipitated PDGF receptor-α from cervical tissue lysates from HPV/E2 mice treated twice daily for 2 wk with imatinib. Western blotting for activated PDGF receptor-α revealed that the phosphotyrosine content of the receptor was reduced by 72% following treatment with imatinib (Figure S1). The first therapeutic trial was initiated at the age of 5 mo, when more than 80% of the mice display overt carcinoma lesions in the cervix [24]. The trial continued for 1 mo (an Intervention Trial). The median tumor volume at this temporally defined endpoint was decreased by 61% following imatinib treatment, demonstrating that this agent can impair the maintenance and growth of preexisting cervical tumors (Figure 2A; Mann-Whitney U test, U = 5, p < 0.05).

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