Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3–5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73–92) ng/ml, 2372 (95% CI, 2121–2623) ng/ml, and 10.6 (95% CI, 7.21–13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675–2292) and a significant increase in MMP-7 levels to 14.6 (7.6–21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.

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Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

International Journal of Cancer ◽

10.1002/ijc.22799 ◽

2007 ◽

Vol 121 (5) ◽

pp. 1066-1071 ◽

Cited By ~ 56

Author(s):

Joan Maurel ◽

Cristina Nadal ◽

Xabier Garcia-Albeniz ◽

Rosa Gallego ◽

Enric Carcereny ◽

...

Keyword(s):

Colorectal Cancer ◽

Matrix Metalloproteinase ◽

Cancer Patients ◽

Poor Prognosis ◽

Advanced Colorectal Cancer ◽

Matrix Metalloproteinase 7 ◽

Colorectal Cancer Patients

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Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies

International Journal of Cancer ◽

10.1002/ijc.24927 ◽

2010 ◽

pp. NA-NA ◽

Cited By ~ 21

Author(s):

Sabina Rinaldi ◽

Rebecca Cleveland ◽

Teresa Norat ◽

Carine Biessy ◽

Sabine Rohrmann ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Risk ◽

Prospective Studies ◽

Meta Analysis ◽

Serum Levels ◽

Colorectal Cancer Risk ◽

Igf I ◽

Igfbp 3

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Serum IGFBP3, IGF-I, and MMP7 changes in advanced colorectal cancer (ACRC) patients (pts) treated with anti-EGFR therapy: A GEMCAD study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15109 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15109-e15109

Author(s):

E. Pineda ◽

C. Pericay ◽

X. García-Albéniz ◽

J. Augé ◽

V. Alonso ◽

...

Keyword(s):

Prognostic Factor ◽

Serum Levels ◽

Continuous Variable ◽

Igf I ◽

Matrix Metalloproteinase 7 ◽

Igf Binding ◽

Third Line ◽

Igf Binding Protein ◽

Apoptotic Effects

e15109 Background: Insulin-like growth factor-I (IGF-I) is a potent mitotic and anti-apoptotic peptide, whereas IGF binding protein-3 (IGFBP3) seems to have pro-apoptotic effects. Matrix metalloproteinase-7 (MMP7), an enzyme with in vitro ability to degrade IGFBP3, has been shown to be a prognostic factor in ACRC. Methods: This is a prospective single cohort traslational study. Pts undergoing second/third line with irinotecan plus anti-EGFR therapy were eligible as cases. Patients with ACRC not undergoing therapy were eligible as controls. IGFBP3 and MMP7 were measured in serum with immunoassays at baseline and at 48h after treatment start. KRAS mutation status in codons 12/13 was determined by sequencing in 53 pts. The primary endpoint is to define the IGFBP3 and MMP7 variation under anti-EGFR therapy. IGFBP3 was used as a continuous variable and MMP7 was used to create two groups by its third quartile. Results: Eighty-five cases and 25 controls were recruited. No significant changes at 48h in IGF-I and IGFBP3 were found, but a significant decrease in MMP7 from 10.8 (95%IC 8.3–13.3) to 8.4 ng/ml (95%IC 6–10.9) was observed in cases (p<0.001) in contrast with controls, where no changes were found. Splitting the sample by the third quartile of MMP7 interesting changes in IGFBP3 variations were found. In the group with low levels of MMP7, IGFBP3 increases from 1,859 to 1,959 ng/ml (p=0.043) 48h after treatment initiation; on the contrary, in the group with high levels of MMP7, IGFBP3 decreases from 1,811 to 1,757 ng/ml (p=0.741). We found no association with IGFBP3 and neither response rate, time to progression nor overall survival. This latter analysis was also done only in pts with wild-type KRAS, without any change in the results. Conclusions: In pts with ACRC treated with anti-EGFR therapy, serum levels of IGFBP3 variations depend on basal MMP7 levels. IGFBP3 failed to be a predictive/prognostic factor in our sample although the limited number of KRAS pts analyzed can influence our results. [Table: see text] No significant financial relationships to disclose.

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Overexpression of Gly56/Gly80/Gly81-Mutant Insulin-Like Growth Factor-Binding Protein-3 in Transgenic Mice

Endocrinology ◽

10.1210/en.2004-0905 ◽

2005 ◽

Vol 146 (3) ◽

pp. 1523-1531 ◽

Cited By ~ 24

Author(s):

Josef V. Silha ◽

Yaoting Gui ◽

Suresh Mishra ◽

Arnold Leckstrom ◽

Pinchas Cohen ◽

...

Keyword(s):

Binding Protein ◽

Serum Levels ◽

Nuclear Antigen ◽

Mouse Strains ◽

Wild Type ◽

Igf I ◽

Independent Effects ◽

Igfbp 3

IGF-independent effects of IGF-binding protein-3 (IGFBP-3) have been demonstrated in vitro; however, the physiological significance of these effects in vivo is unclear. We generated two transgenic (Tg) mouse strains that overexpress a human Gly56/Gly80/Gly81-mutant IGFBP-3 cDNA. This mutant has a markedly reduced affinity for the IGFs, but retains the IGF-independent effects. Serum levels of mutant IGFBP-3 were 156 ± 12 and 400 ± 24 ng/ml in hemizygous mice of strains 5005 and 5012, respectively. When Tg and wild-type mice were compared, there was no reduction in birth weight, litter size, or postnatal growth. Despite differences in transgene expression in various tissues, relative organ weight was similar in Tg and wild-type mice, with exception of brain, where a modest reduction in brain weight was observed in the high-expressing 5012 lineage. There was also a significant reduction in proliferating cell nuclear antigen-staining cells observed in the periventricular region of the developing brain in embryonic d 18 Tg embryos. In the higher expressing 5012 Tg strain, IGF-I and murine IGFBP-3 levels, marker of GH action were increased. Furthermore, there was a positive correlation between mutant IGFBP-3 levels and IGF-I levels and between mutant IGFBP-3 levels and murine IGFBP-3 (P = 0.002 and P < 0.001, respectively). These data indicate that overexpression of mutant IGFBP-3 is not associated with growth retardation. The higher levels of IGF-I and murine IGFBP-3 in the 5012 Tg strain suggest that the growth inhibitory effect of mutant IGFBP-3 may be compensated for by other mechanisms.

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