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A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain.

Selvaraj D, Gangadharan V, Michalski CW, Kurejova M, Stösser S, Srivastava K, Schweizerhof M, Waltenberger J, Ferrara N, Heppenstall P, Shibuya M, Augustin HG, Kuner R - Cancer Cell (2015)

Bottom Line: Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life.Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain.These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.

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Role of VEGFR1 in Cancer Pain following Hind Paw Implantation of C57BL6-Isogenic Lewis Lung Carcinoma Cells(A) Western blot analysis on DRGs from SNS-Vegfr1−/− and Vegfr1fl/fl (control) mice.(B–G) Analysis of SNS-Vegfr1−/− and Vegfr1fl/fl mice (n = 6–8 mice/group) with respect to intraplantar VEGF-A-induced mechanical (B) and thermal hypersensitivity (C), tumor-associated hypersensitivity (D), tumor-induced hypertrophy and sprouting of PGP-9.5-immunoreactive sensory nerves (E and F), and tumor growth (G), including negative control for immunostaining and an H&E-stained section.(H and I) Tumor-induced mechanical hypersensitivity (H) and tumor growth (I) in VEGFR1-Tk−/− and WT mice.∗p < 0.05 as compared with sham in (F) and compared with basal in other panels, ANOVA followed post hoc Fisher’s test; in (D) and (H), ANOVA for repeated-measures was performed; †p < 0.05 as compared with corresponding control group, ANOVA for random measures followed by post hoc Fisher’s test. Scale bar represents 50 μm in (E). Data are presented as mean ± SEM.
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fig5: Role of VEGFR1 in Cancer Pain following Hind Paw Implantation of C57BL6-Isogenic Lewis Lung Carcinoma Cells(A) Western blot analysis on DRGs from SNS-Vegfr1−/− and Vegfr1fl/fl (control) mice.(B–G) Analysis of SNS-Vegfr1−/− and Vegfr1fl/fl mice (n = 6–8 mice/group) with respect to intraplantar VEGF-A-induced mechanical (B) and thermal hypersensitivity (C), tumor-associated hypersensitivity (D), tumor-induced hypertrophy and sprouting of PGP-9.5-immunoreactive sensory nerves (E and F), and tumor growth (G), including negative control for immunostaining and an H&E-stained section.(H and I) Tumor-induced mechanical hypersensitivity (H) and tumor growth (I) in VEGFR1-Tk−/− and WT mice.∗p < 0.05 as compared with sham in (F) and compared with basal in other panels, ANOVA followed post hoc Fisher’s test; in (D) and (H), ANOVA for repeated-measures was performed; †p < 0.05 as compared with corresponding control group, ANOVA for random measures followed by post hoc Fisher’s test. Scale bar represents 50 μm in (E). Data are presented as mean ± SEM.

Mentions: To further obtain evidence from genetic models and to specifically delineate the contribution of VEGFR1 expressed in nociceptive neurons of the DRG, we generated a line of transgenic mice conditionally lacking VEGFR1 in nociceptive neurons by mating Vegfr1fl/fl mice (Ambati et al., 2006) with SNS-Cre mice (Agarwal et al., 2004) (SNS-Vegfr1−/− mice). Western blot analysis (Figure 5A) confirmed a decrease in DRG expression of VEGFR1 (55% ± 2.8% of the value in Vegfr1fl/fl mice). Intraplantar VEGF-A-induced mechanical and thermal hypersensitivity was nearly entirely lost in SNS-Vegfr1−/− mice as compared with their WT littermates, indicating a requirement for VEGFR1 expressed in peripheral nociceptors (Figures 5B and 5C).


A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain.

Selvaraj D, Gangadharan V, Michalski CW, Kurejova M, Stösser S, Srivastava K, Schweizerhof M, Waltenberger J, Ferrara N, Heppenstall P, Shibuya M, Augustin HG, Kuner R - Cancer Cell (2015)

Role of VEGFR1 in Cancer Pain following Hind Paw Implantation of C57BL6-Isogenic Lewis Lung Carcinoma Cells(A) Western blot analysis on DRGs from SNS-Vegfr1−/− and Vegfr1fl/fl (control) mice.(B–G) Analysis of SNS-Vegfr1−/− and Vegfr1fl/fl mice (n = 6–8 mice/group) with respect to intraplantar VEGF-A-induced mechanical (B) and thermal hypersensitivity (C), tumor-associated hypersensitivity (D), tumor-induced hypertrophy and sprouting of PGP-9.5-immunoreactive sensory nerves (E and F), and tumor growth (G), including negative control for immunostaining and an H&E-stained section.(H and I) Tumor-induced mechanical hypersensitivity (H) and tumor growth (I) in VEGFR1-Tk−/− and WT mice.∗p < 0.05 as compared with sham in (F) and compared with basal in other panels, ANOVA followed post hoc Fisher’s test; in (D) and (H), ANOVA for repeated-measures was performed; †p < 0.05 as compared with corresponding control group, ANOVA for random measures followed by post hoc Fisher’s test. Scale bar represents 50 μm in (E). Data are presented as mean ± SEM.
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fig5: Role of VEGFR1 in Cancer Pain following Hind Paw Implantation of C57BL6-Isogenic Lewis Lung Carcinoma Cells(A) Western blot analysis on DRGs from SNS-Vegfr1−/− and Vegfr1fl/fl (control) mice.(B–G) Analysis of SNS-Vegfr1−/− and Vegfr1fl/fl mice (n = 6–8 mice/group) with respect to intraplantar VEGF-A-induced mechanical (B) and thermal hypersensitivity (C), tumor-associated hypersensitivity (D), tumor-induced hypertrophy and sprouting of PGP-9.5-immunoreactive sensory nerves (E and F), and tumor growth (G), including negative control for immunostaining and an H&E-stained section.(H and I) Tumor-induced mechanical hypersensitivity (H) and tumor growth (I) in VEGFR1-Tk−/− and WT mice.∗p < 0.05 as compared with sham in (F) and compared with basal in other panels, ANOVA followed post hoc Fisher’s test; in (D) and (H), ANOVA for repeated-measures was performed; †p < 0.05 as compared with corresponding control group, ANOVA for random measures followed by post hoc Fisher’s test. Scale bar represents 50 μm in (E). Data are presented as mean ± SEM.
Mentions: To further obtain evidence from genetic models and to specifically delineate the contribution of VEGFR1 expressed in nociceptive neurons of the DRG, we generated a line of transgenic mice conditionally lacking VEGFR1 in nociceptive neurons by mating Vegfr1fl/fl mice (Ambati et al., 2006) with SNS-Cre mice (Agarwal et al., 2004) (SNS-Vegfr1−/− mice). Western blot analysis (Figure 5A) confirmed a decrease in DRG expression of VEGFR1 (55% ± 2.8% of the value in Vegfr1fl/fl mice). Intraplantar VEGF-A-induced mechanical and thermal hypersensitivity was nearly entirely lost in SNS-Vegfr1−/− mice as compared with their WT littermates, indicating a requirement for VEGFR1 expressed in peripheral nociceptors (Figures 5B and 5C).

Bottom Line: Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life.Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain.These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.

Show MeSH
Related in: MedlinePlus