3479

IGF1

insulin-like growth factor 1 (somatomedin C);IGF1;insulin-like growth factor 1 (somatomedin C)

IGF-IA|IGF-IB|MGF|insulin-like growth factor I|insulin-like growth factor IA|insulin-like growth factor IB|mechano growth factor|somatomedin-C

12q23.2

protein-coding

AIM: To investigate the expression of insulin-like growth factor-1 (IGF-1)/insulin-like growth factor-1 receptor (IGF-1R) in colorectal cancer (CRC) tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis. METHODS: Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density (LVD) in 40 CRC specimens. The correlation between IGF-1/IGF-1R and LVD was investigated. Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays. A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo. RESULTS: Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis (r = 0.715 and 0.569, respectively, P < 0.05) and tumor TNM stage (r = 0.731 and 0.609, P < 0.05). A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis (r = 0.405, P < 0.05). A positive correlation was found between LVD and IGF-1R expression (r = 0.437, P < 0.05). Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells. In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts. CONCLUSION: IGF-1/IGF-1R signaling induces tumor-associated lymphangiogenesis and contributes to lymphatic metastasis of CRC.

OBJECTIVE: To investigate the expression of matrix metalloproteinase-2 (MMP-2) and insulin-like growth factor-1 (IGF-1) in gastric carcinoma and their clinicopathological significance. METHODS: expressions of MMP-2 and IGF-1 were examined by using immunohistochemical SP staining and cross-compared with clinicopathological features of gastric carcinoma. RESULTS: High expression of MMP-2 and IGF-1 were observed in 70.4% (307/436) and 49.5% (216/436) of gastric carcinoma tissues respectively, significantly higher than those in non-tumor gastric mucosa (3.3% and 5.4%, respectively; all P < 0.05). The high expression rate of MMP-2 and IGF-1 were significantly associated with the patient age, tumor size, tumor location, Lauren classification, TNM staging, depth of tumor infiltration, presence of vessel invasion, lymph node and distant metastasis (all P < 0.05). In addition, the expression of MMP-2 was positively linked with the expression level of IGF-1 (P < 0.05). Univariate analysis showed that high expression of MMP-2, was significantly associated with poor prognosis of tumor of TNM stage I and II (all P < 0.05), high expression of IGF-1 was significantly correlated with poor prognosis of patients with TNM stage I, II and III tumor (all P < 0.05). Cox multivariate analysis indicated that the high expressions of MMP-2 and IGF-1 could be independent prognostic indices for gastric carcinoma. CONCLUSIONS: High expression of MMP-2 and IGF-1 proteins are significantly correlated with the invasion and metastasis of gastric carcinoma, it is helpful to simultaneously detect the expressions of MMP-2 and IGF-1 proteins in predicting prognosis of patients with gastric carcinoma.

BACKGROUND/AIM: There were two aims in the present study. The first was to evaluate the usefulness of insulin-like growth factor 1 (IGF1) for melanoma detection. The second was to correlate changes of serum levels of IGF1 with the Breslow score and sentinel node metastasis positivity. PATIENTS AND METHODS: We examined a group of 216 cases, 77 patients with melanomas and 139 healthy probands. We determined the serum IGF1 levels of each patient using an IRMA radioisotope IGF1 assay kit. Serum samples were collected prior to surgery or any other form of treatment. All melanoma diagnoses were histologically verified. RESULTS AND DISCUSSION: Based on the statistical evaluation between the melanoma group and group of healthy individuals, we observed statistically significant differences in IGF1 serum levels. The median IGF1 levels in the melanoma group was 154.1 ng/ml compared to 111.2 ng/ml in the group of healthy individuals (p=0.0036). The changes of the IGF1 levels related to the Breslow score categories were statistically significant (p=0.0027). Lastly, we compared the results between the positive and negative metastatic affection of the sentinel nodes. The median IGF1 levels in the negative group was 173.5 ng/ml compared to 205.8 ng/ml in the positive group. This difference was statistically significant (p=0.0407). CONCLUSION: Serum levels of IGF1 were significantly higher in patients diagnosed with melanoma compared to the healthy control group. The changes of the IGF1 levels related to the Breslow score categories were statistically significant. Serum levels of IGF1 were significantly higher in the group with the positive metastatic affection of the sentinel nodes than in negative patients.

The KCl cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. This study stresses the important role of KCC4 in tumor malignant behavior. Real-time reverse transcription-PCR on samples collected by laser microdissection and immunofluorescent stainings with different KCC isoform antibodies indicate that KCC4 is abundant in metastatic cervical and ovarian cancer tissues. Insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) stimulate KCC4 recruitment from a presumably inactive cytoplasmic pool of endoplasmic reticulum and Golgi to plasma membrane along actin cytoskeleton that is significantly inhibited by LY294002 and wortmannin. Throughout the trafficking process, KCC4 is incorporated into lipid rafts that function as a platform for the association between KCC4 and myosin Va, an actin-dependent motor protein. KCC4 and ezrin, a membrane cytoskeleton linker, colocalize at lamellipodia of migratory cancer cells. Interference with KCC activity by either an inhibitor or a dominant-negative loss-of-function mutant profoundly suppressed the IGF-I-induced membrane trafficking of KCC4 and the structural interaction between KCC4 and ezrin near the cell surface. Endogenous cancer cell invasiveness was significantly attenuated by small interfering RNA targeting KCC4, and the residual invasiveness was much less sensitive to IGF-I or EGF stimulation. In the metastatic cancer tissues, KCC4 colocalizes with IGF-I or EGF, indicating a likely in vivo stimulation of KCC4 function by growth factors. Thus, blockade of KCC4 trafficking and surface expression may provide a potential target for the prevention of IGF-I- or EGF-dependent cancer spread.

BACKGROUND: cancer patients frequently suffer from weight loss and systemic inflammation in the context of advanced disease, which is related to adverse outcome. Insulin-like growth factor (IGF)-I is an anabolic molecule implicated in the maintenance of muscle mass and cancer growth. We investigated potential correlations of IGF-I with an inflammatory and weight loss status and with clinical outcome. METHODS: Baseline IGF-I plasma levels were measured in 77 patients (66 males, median age 65.5 +/- 10.6 years), diagnosed with metastatic non-small cell lung cancer, and were correlated with serum albumin and C-reactive protein (CRP) levels, weight loss history, treatment response and overall survival. RESULTS: IGF-I correlated with age (p = 0.01), histologic subtype (p = 0.019), albumin (p < 0.001) and CRP (p < 0.001). In univariate analysis, gender (p = 0.005), smoking status (p = 0.012), albumin (p = 0.034) and IGF-I (p = 0.017) were related to time to progression, while IGF-I (p = 0.003), gender (p = 0.049) and smoking status (p = 0.003) retained their significance in multivariate analysis. Age (p = 0.005), gender (p = 0.029), weight loss (p = 0.009), performance status (p < 0.001), number of metastatic sites (p = 0.004), albumin (p = 0.008), CRP (p = 0.022) and IGF-I (p = 0.042) were associated with overall survival, although only gender (p = 0.013), weight loss (p = 0.027), performance status (p = 0.015) and number of metastatic sites (p = 0.021) emerged as independent prognostic factors. CONCLUSION: IGF-I correlates with systemic inflammation and seems to play an independent predictive role in metastatic non-small cell lung cancer.

BACKGROUND: Type-1 insulin-like growth factor (IGF-1) up-regulates cell proliferation and invasiveness through activation of PI3K/Akt signaling pathway. IGF-1 also down-regulates the tumor suppressor chromosome 10 (PTEN). We investigated the mechanism by which IGF-1 affects cell proliferation and invasion by suppression of PTEN phosphorylation and interaction with PI3K/PTEN/Akt/NF-small ka, CyrillicB signaling pathway in pancreatic cancer. MATERIALS AND METHODS: The expression of IGF-1 receptor (IGF-1R) and PTEN in five pancreatic cancer cell lines was determined by RT-PCR and Western blot. Proliferation and invasion were investigated by WST-1 assay and Matrigel-double chamber assay. Pancreatic cancer cells were transfected with PTEN siRNA to investigate which signaling pathway correlates in regulation of cancer cell proliferation and invasion. RESULTS: Five pancreatic cancer cell lines expressed PTEN and IGF-1R in mRNA and protein levels. Suppression of PTEN phosphorylation strongly enhanced cell proliferation and invasion stimulated with IGF-1 via activation of PI3K/Akt/NF-small ka, CyrillicB signaling pathway. In addition, knockdown of PTEN by siRNA transfection also enhanced activation of PI3K/Akt/NF-small ka, CyrillicB pathway, subsequently up-regulating cell invasiveness and proliferation. CONCLUSIONS: The IGF-1/PI3K/PTEN/Akt/NF-small ka, CyrillicB cascade may be a key pathway stimulating metastasis of pancreatic cancer cells. We suggest that interfering with the functions of IGF-1/PI3K/Akt/NF-small ka, CyrillicB might be a novel therapeutic approach to inhibit aggressive spread of pancreatic cancer.

BACKGROUND: The insulin-like growth factor-1 (IGF-1) plays an important role in growth of prostate cancer (PCa) cells and facilitating the development and progression of PCa. This study aimed to evaluate the association of polymorphisms in three linkage disequilibrium (LD) blocks of the IGF-1 on the survival of metastatic PCa patients. METHODS: A total of 215 patients with bone metastases at initial presentation were included in this study. The cytosine-adenine (CA) repeat polymorphism and rs12423791 were selected as representative polymorphisms in the LD blocks 1 and 2, respectively. Haplotype in the LD block 3 was analyzed using two tag single nucleotide polymorphisms (SNPs), rs6220 and rs7136446. cancer-specific survival rate was estimated from the Kaplan-Meier curve, and the survival data were compared using the log-rank test. RESULTS: cancer-specific survival was significantly associated with the CA repeat polymorphism, rs12423791, and rs6220 (P = 0.013, 0.014, and 0.014, respectively). Although rs7136446 had no significant association with survival, the haplotype in the LD block 3 was significantly associated with cancer-specific survival (P = 0.0003). When the sum of the risk genetic factors in each LD block (19-repeat allele, C allele of rs12423791, or C-T haplotype) was considered, patients with all the risk factors had significantly shorter cancer specific-survival than those with 0-2 risk factors (P = 0.0003). CONCLUSIONS: Polymorphisms in the IGF-1, especially a haplotype in the LD block 3, are assumed to be genetic markers predicting the outcome of metastatic PCa.

BACKGROUND: Insulin-like growth factor I (IGF-I), a potent proximal tubule cell (PTC) mitogen, has been implicated in the progression of many human cancers. Our previous work on human renal tissues has suggested that IGF-I and several of its binding proteins (IGFBP-3 and -6) are up-regulated in clear cell renal cell carcinoma (RCC). METHODS: To further elucidate the role of IGF-I and IGFBPs in RCC growth, immunohistochemistry, thymidine incorporation, and Western analysis were performed in primary cultures of normal PTC (priPTC) and clear-cell RCC (priRCC), as well as in SN12K1 cells (a cell line derived from metastatic RCC). RESULTS: By immunohistochemistry, IGFBP-3 and IGF-I were prominently expressed in SN12K1 cells, and weakly expressed in priPTC and priRCC. Incubation with 100 ng/mL IGF-I significantly augmented DNA synthesis by priPTC (mean +/- SD 120.7%+/- 19.7% of controls, P < 0.05), priRCC (238.7%+/- 279.9% of controls, P < 0.01), and SN12K1(120.0%+/- 22.9% of controls, P < 0.05). Neutralizing antibodies to IGF-I and IGF-I receptor significantly suppressed SN12K1 growth (81.9%+/- 13.5% of control, P < 0.01 and 87.4%+/- 16.2% of control, P < 0.05, respectively). Removal of endogenous IGFBP-3 by an anti-IGFBP-3 increased SN12K1 DNA synthesis (243.9%+/- 35.3% of control, P < 0.001), which was partially abrogated by coincubation with exogenous IGFBP-3 (135.97%+/- 5.9% of controls, P < 0.001). Using Western analysis, IGFBP-3 expression was enhanced in IGF-I-stimulated SN12K1 cells exposed to exogenous IGF-I. Coincubation with anti-IGFBP-3 further enhanced IGF-I-induced DNA synthesis. CONCLUSION: RCC cells express IGF-I and IGFBP-3, and are responsive to exogenous IGF-I stimulation. Moreover, in SN12K1 cells (derived from metastatic RCC), autocrine IGF-I and IGFBP-3 actions, respectively, stimulated and inhibited growth. These results suggest that IGF-I and IGFBP-3 may be potential candidates for therapeutic manipulation in patients with advanced RCC.