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Insulin-like-growth-factor-binding-protein-3 (IGFBP-3) contrasts melanoma progression in vitro and in vivo.

Naspi A, Panasiti V, Abbate F, Roberti V, Devirgiliis V, Curzio M, Borghi M, Lozupone F, Carotti S, Morini S, Gaudio E, Calvieri S, Londei P - PLoS ONE (2014)

Bottom Line: Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival.In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival.In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

View Article: PubMed Central - PubMed

Affiliation: Istituto Pasteur-Fondazione Cenci-Bolognetti, Dpt. Biotecnologie Cellulari ed Ematologia, University of Rome Sapienza, Rome, Italy.

ABSTRACT
Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

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Low IGFBP-3 levels correlate with melanoma progression and patients' survival.(A) Kaplan-Meier survival curve of melanoma patients having seric IGFPB-3 concentration higher (red line) or lower (blue line) than 4.6 ng/mL. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (B) Kaplan-Meier survival curve of patients with IGF-1/IGFBP-3 ratio higher (red line) or lower (blue line) than 6.2. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (C) Mean IGFBP-3 serum levels measured twice (28 patients) during the follow-up. Orange boxes: Patients with stable disease. Blue boxes: patients with progressive disease. P value was calculated by ANOVA test. (D,G) IGFBP-3 immuno-staining in tissue samples from primary melanomas. (E, H) IGFBP-3 immuno-staining in tissue samples from metastatic melanomas. The asterisks indicate positive melanocytes nests in primary melanoma. The arrows indicate IGFBP-3 positive stromal cells. Original magnification, X100. (F,I) Graphic data processing for total (upper panel) and stromal (lower panel) IGFBP-3 immuno-staining score. 20 different samples were taken in each case and the number of IGFBP-3 positive cells was separately counted by two researchers. For each slide, at least 7–10 microscopic fields were randomly chosen. The immuno-histochemical score was evaluated as described in the Methods separately for melanocytic and stromal cells and expressed as tumour and stromal score respectively. A total score was derived for each sample as the sum of tumour and stromal score. Central boxes correspond to values from lower to upper quartile (25th–75th percentile). Middle lines show median. Vertical lines extend from minimum to maximum value. P value calculated by Mann-Whitney U test.
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pone-0098641-g001: Low IGFBP-3 levels correlate with melanoma progression and patients' survival.(A) Kaplan-Meier survival curve of melanoma patients having seric IGFPB-3 concentration higher (red line) or lower (blue line) than 4.6 ng/mL. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (B) Kaplan-Meier survival curve of patients with IGF-1/IGFBP-3 ratio higher (red line) or lower (blue line) than 6.2. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (C) Mean IGFBP-3 serum levels measured twice (28 patients) during the follow-up. Orange boxes: Patients with stable disease. Blue boxes: patients with progressive disease. P value was calculated by ANOVA test. (D,G) IGFBP-3 immuno-staining in tissue samples from primary melanomas. (E, H) IGFBP-3 immuno-staining in tissue samples from metastatic melanomas. The asterisks indicate positive melanocytes nests in primary melanoma. The arrows indicate IGFBP-3 positive stromal cells. Original magnification, X100. (F,I) Graphic data processing for total (upper panel) and stromal (lower panel) IGFBP-3 immuno-staining score. 20 different samples were taken in each case and the number of IGFBP-3 positive cells was separately counted by two researchers. For each slide, at least 7–10 microscopic fields were randomly chosen. The immuno-histochemical score was evaluated as described in the Methods separately for melanocytic and stromal cells and expressed as tumour and stromal score respectively. A total score was derived for each sample as the sum of tumour and stromal score. Central boxes correspond to values from lower to upper quartile (25th–75th percentile). Middle lines show median. Vertical lines extend from minimum to maximum value. P value calculated by Mann-Whitney U test.

Mentions: After normalizing for sex and age, IGFBP-3 levels were also significantly correlated with survival. 56.7% of the patients with low IGFBP-3 survived for at least 18 months, compared to 88.3% of those with high IGFBP-3 (P = 0.011) (Fig. 1A). The same was true for the ratio IGF1/IGFBP-3. 49% of patients with a higher ratio survived for 18 months, compared to 90.1% of those with a lower ratio (P = 0.0033) (Fig. 1B). In contrast, IGF-1 levels were not correlated with either disease stage or survival.


Insulin-like-growth-factor-binding-protein-3 (IGFBP-3) contrasts melanoma progression in vitro and in vivo.

Naspi A, Panasiti V, Abbate F, Roberti V, Devirgiliis V, Curzio M, Borghi M, Lozupone F, Carotti S, Morini S, Gaudio E, Calvieri S, Londei P - PLoS ONE (2014)

Low IGFBP-3 levels correlate with melanoma progression and patients' survival.(A) Kaplan-Meier survival curve of melanoma patients having seric IGFPB-3 concentration higher (red line) or lower (blue line) than 4.6 ng/mL. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (B) Kaplan-Meier survival curve of patients with IGF-1/IGFBP-3 ratio higher (red line) or lower (blue line) than 6.2. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (C) Mean IGFBP-3 serum levels measured twice (28 patients) during the follow-up. Orange boxes: Patients with stable disease. Blue boxes: patients with progressive disease. P value was calculated by ANOVA test. (D,G) IGFBP-3 immuno-staining in tissue samples from primary melanomas. (E, H) IGFBP-3 immuno-staining in tissue samples from metastatic melanomas. The asterisks indicate positive melanocytes nests in primary melanoma. The arrows indicate IGFBP-3 positive stromal cells. Original magnification, X100. (F,I) Graphic data processing for total (upper panel) and stromal (lower panel) IGFBP-3 immuno-staining score. 20 different samples were taken in each case and the number of IGFBP-3 positive cells was separately counted by two researchers. For each slide, at least 7–10 microscopic fields were randomly chosen. The immuno-histochemical score was evaluated as described in the Methods separately for melanocytic and stromal cells and expressed as tumour and stromal score respectively. A total score was derived for each sample as the sum of tumour and stromal score. Central boxes correspond to values from lower to upper quartile (25th–75th percentile). Middle lines show median. Vertical lines extend from minimum to maximum value. P value calculated by Mann-Whitney U test.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4048209&req=5

pone-0098641-g001: Low IGFBP-3 levels correlate with melanoma progression and patients' survival.(A) Kaplan-Meier survival curve of melanoma patients having seric IGFPB-3 concentration higher (red line) or lower (blue line) than 4.6 ng/mL. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (B) Kaplan-Meier survival curve of patients with IGF-1/IGFBP-3 ratio higher (red line) or lower (blue line) than 6.2. Cut-off value was chosen by ROC curve. P value was calculated by log rank test. (C) Mean IGFBP-3 serum levels measured twice (28 patients) during the follow-up. Orange boxes: Patients with stable disease. Blue boxes: patients with progressive disease. P value was calculated by ANOVA test. (D,G) IGFBP-3 immuno-staining in tissue samples from primary melanomas. (E, H) IGFBP-3 immuno-staining in tissue samples from metastatic melanomas. The asterisks indicate positive melanocytes nests in primary melanoma. The arrows indicate IGFBP-3 positive stromal cells. Original magnification, X100. (F,I) Graphic data processing for total (upper panel) and stromal (lower panel) IGFBP-3 immuno-staining score. 20 different samples were taken in each case and the number of IGFBP-3 positive cells was separately counted by two researchers. For each slide, at least 7–10 microscopic fields were randomly chosen. The immuno-histochemical score was evaluated as described in the Methods separately for melanocytic and stromal cells and expressed as tumour and stromal score respectively. A total score was derived for each sample as the sum of tumour and stromal score. Central boxes correspond to values from lower to upper quartile (25th–75th percentile). Middle lines show median. Vertical lines extend from minimum to maximum value. P value calculated by Mann-Whitney U test.
Mentions: After normalizing for sex and age, IGFBP-3 levels were also significantly correlated with survival. 56.7% of the patients with low IGFBP-3 survived for at least 18 months, compared to 88.3% of those with high IGFBP-3 (P = 0.011) (Fig. 1A). The same was true for the ratio IGF1/IGFBP-3. 49% of patients with a higher ratio survived for 18 months, compared to 90.1% of those with a lower ratio (P = 0.0033) (Fig. 1B). In contrast, IGF-1 levels were not correlated with either disease stage or survival.

Bottom Line: Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival.In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival.In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

View Article: PubMed Central - PubMed

Affiliation: Istituto Pasteur-Fondazione Cenci-Bolognetti, Dpt. Biotecnologie Cellulari ed Ematologia, University of Rome Sapienza, Rome, Italy.

ABSTRACT
Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

Show MeSH
Related in: MedlinePlus