Novel stimulatory role for insulin-like growth factor binding protein-2 in prostate cancer cells

The insulin-like growth factor (IGF) axis is a complex system composed of 2 mitogenic ligands, IGF-I and -II, 2 receptors, IGF-1R and IGF-2R, and 6 binding proteins, IGFBP-1 to -6. The IGFBPs exert their actions through their regulation of IGF bioavailability for IGF receptors. In addition, some IGFBPs have also been found to have direct cellular actions independent of IGFs. IGFBP-2 is a major IGFBP in the prostate and in seminal fluid. IGFBP-2 levels, which are elevated in many malignancies, are markedly increased in prostate cancer, and show a positive correlation with prostate specific antigen (PSA) and prostate tumor aggressiveness. We investigated the potential role of IGFBP-2 in the pathogenesis of prostate cancer by evaluating its ability to stimulate growth and the expression and activity of the nuclear enzyme, telomerase. We found IGFBP-2 to have a modest suppressive effect on the growth of primary cultures of normal prostate epithelial cells and a potent IGF-antagonistic effect in these cells, similar to previous reports on the inhibitory nature of this molecule. Surprisingly, IGFBP-2 had a potent stimulatory effect on growth of LAPC-4 prostate cancer cells, an effect that was more pronounced in the absence of androgens. IGFBP-2 growth stimulation of LAPC-4 cells was completely blocked by MAP-kinase inhibitors and partially blocked by PI3-kinase inhibitors. IGFBP-2 stimulation of LAPC-4 cell growth seen in serum-free conditions was lost in the presence of 10% FBS. IGFBP-2 also had a growth stimulatory effect on DU 145 prostate cancer cells. IGFBP-2 significantly stimulated telomerase activity in LAPC-4 cells in the absence of androgens. In addition, IGFBP-2 significantly stimulated hTERT expression and telomerase activity in DU 145 cells. Thus, we demonstrated an inhibitory effect of IGFBP-2 on non-malignant prostate cells, but showed it to be stimulatory for prostate cancer cells in a MAP-kinase and androgen-modulated process. In conclusion, IGFBP-2 may play a role in the progression, but not in the initiation of the prostate cancer disease process, suggesting the existence of a molecular switch transitioning IGFBP-2 from a growth inhibitor to a pro-carcinogenic molecule.     

Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues.

To assess the role of insulin-like growth factors (IGFs) in growth and transformation of normal (myometrium) and tumorous smooth muscle cell (SMC) tissues, in situ hybridization (ISH) analysis for insulin-like growth factor I and II (IGF-I and IGF-II) mRNAs was combined with detection of IGF peptides, their receptors and IGF binding protein-3 (IGFBP-3). mRNAs for both IGFs were detected in smooth muscle cells in normal, benign and malignant SMC tissues, together with the IGF peptides, both IGF receptors and IGFBP-3. This suggests an autocrine role for both IGFs. Leiomyomas had higher IGF-I peptide levels and higher levels of type I IGF receptors than myometrium, supporting the idea that IGFs play a role in the growth and transformation of these tumours. Low-grade leiomyosarcomas contained more IGF-II mRNAs than myometrium and leiomyoma, fewer type II IGF/mannose 6-phosphate receptors and less IGFBP-3 than myometrium and, in addition, fewer IGF-I mRNAs and type I IGF receptors than leiomyoma. Intermediate- and high-grade leiomyosarcomas had intermediate levels of IGF-II mRNAs and peptide, ranging between those in myometrium and low-grade leiomyosarcomas. Thus, growth and transformation of leiomyosarcomas may be regulated by IGF-II, although more markedly in low-grade than in high-grade leiomyosarcomas. In conclusion, the various categories of SMC tissues are associated with a distinct expression pattern of the IGF system. This suggests that each category of SMC tumours arises as a distinct entity and that there is no progression of transformation in these tissues.     

Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action.

BACKGROUND: The insulin-like growth factors (IGFs) play an important role in normal growth and development. Evidence suggests they may also regulate the growth of several cancer cell types. This regulation is mediated by interactions between the receptors and ligands. There is now ample evidence to suggest that these interactions are also influenced by extracellular IGF-binding proteins (IGFBPs). Six different IGFBPs have been cloned. Some species may act to inhibit the mitogenic effects of the IGFs. Since breast cancer cells are responsive to the IGFs, it is possible that regulated expression of the IGFBPs affects tumor growth. Furthermore, inhibitory binding proteins could be used as neutralizers of IGF action. PURPOSE: We conducted this study to fully characterize the expression and hormonal regulation of IGF-binding protein expression in human MCF-7 breast cancer cells and to test the ability of purified IGFBP-1 to inhibit IGF-I action. METHODS: We used ribonuclease protection assays and Western ligand blotting to examine IGFBP expression in MCF-7 cells. The effect of IGF-I, IGFBP-1, and 17 beta-estradiol on serum-free cell growth was also studied. RESULTS: MCF-7 cells expressed IGFBP-2, IGFBP-4, and IGFBP-5 RNA and protein. These cells are dependent on estrogen for growth. In short-term culture, IGF-I can substitute for estrogen. Concomitant addition of IGF-I and estrogen enhanced stimulation above the level achieved by either factor alone. Estrogen also increased IGFBP production, making it unlikely that the IGFBPs induced by estrogen in MCF-7 cells could function as major inhibitors of IGF action. In contrast, exogenous addition of IGFBP-1 could block IGF-I-induced mitogenesis; this effect was reversible by excess IGF-I. CONCLUSIONS: The studies suggest that cancer cell growth may be regulated by endogenous IGFBP expression. Furthermore, the exogenous addition of the IGFBP-1 blocked IGF-I action and potentially could be used as a pharmacologic inhibitor of IGF action.     

Microencapsulated octreotide pamoate in advanced gastrointestinal and pancreatic cancer: a phase I study.

Fourteen patients suffering from advanced colorectal (n = 7), pancreatic (n = 4) or gastric (n = 3) carcinomas received treatment with microencapsulated octreotide pamoate 90 mg i.m. every 4 weeks (n = 4), 160 mg i.m. every 4 weeks (n = 4) or 160 mg i.m. every 2 weeks (n = 6). Two patients had stable disease, one for 4 and one for 6 months. Plasma insulin-like growth factor (IGF)-I decreased by 49-53%, IGF-II by 27-37% and total IGF-binding protein (IGFBP)-3 by 16-19%, whereas IGFBP-1 increased by 35-55%. Insulin and C-peptide levels decreased by 29-38% and 41-46% respectively. A non-significant decrease in urinary GH secretion and an increase in the ratio of fragmented to intact IGFBP-3 as well as IGFBP-3 protease activity was seen. The increase in IGFBP-3 fragmentation correlated negatively with alterations in IGF-I and IGF-II (P < 0.05). We conclude that microencapsulated octreotide administered in doses up to 160 mg every 2 weeks is well tolerated and has pronounced effects on several components of the IGF system in plasma. In addition, changes in IGFBP-3 protease activity because of cancer may contribute to alterations in IGF-I and -II, indicating the importance of measuring this parameter in addition to IGFs and IGFBPs when evaluating alterations in IGF-I.     

Histamine-stimulated expression of insulin-like growth factors in human glioma cells.

Glioma tumour growth is associated with the expression of insulin-like growth factors I and II (IGFs) and of both type I and type II IGF receptors. It has also been shown that IGFs can stimulate proliferation of cultured glioma cells. We previously reported that histamine too can stimulate the growth of glioma cells in vitro. In this report, we study whether the histamine-induced growth of G47 glioma cells is mediated by the IGFs. We found that histamine stimulates the expression of both IGF-I and IGF-II mRNAs, as determined by a semiquantitative in situ hybridization analysis. Furthermore, incubation of G47 cells with histamine also induced cellular immunostaining for IGF-II. It could be shown that IGF-I-stimulated proliferation is inhibited by IGFBP-3, which decreases the availability of IGFs for binding to the IGF receptors, and by beta-galactosidase, which may decrease IGF binding to the type II IGF receptor, but is not inhibited by the anti-type I IGF receptor monoclonal antibody alphaIR3. However, neither IGFBP-3 nor beta-galactosidase nor alphaIR3 inhibited the histamine-induced proliferation. These results show that the growth-stimulatory effect of histamine is accompanied by the induction of IGFs. This histamine-induced growth stimulation is not mediated by activation of cell surface IGF receptors, although intracrine activation of type II IGF receptors may be involved.     

Insulin-like growth factors and breast cancer risk in Chinese women.

Insulin-like growth factor (IGF)-I has mitogenic and antiapoptotic effects on breast cancer cells. High-circulating IGF-I was found to be associated with increased risk of breast cancer in several previous epidemiological studies, mostly conducted in the Caucasian populations. Little is known about the association between IGF and breast cancer in Asian women whose dietary habits differ considerably from their Caucasian counterparts. A population-based case-control study was conducted to assess the associations of IGFs and IGF binding protein-3, a major IGF binding protein in the circulation, with breast cancer risk in Chinese women. The study included 300 incident breast cancer patients diagnosed between August 1996 and March 1998 in Shanghai and 300 age- and menopause-matched controls selected randomly from the general population. Plasma levels of IGF-I, IGF-II, and IGFBP-3 were measured using commercial ELISA kits (Diagnostic Systems Laboratories, Webster, TX). Conditional logistic regression analysis was performed to examine the association between IGF and breast cancer risk after adjusting for potential confounding factors. Breast cancer patients had higher plasma levels of IGF-I and IGFBP-3. A dose-response relationship was observed between breast cancer risk and the level of IGF-I or IGFBP-3. The adjusted odds ratios were 2.01 (95% confidence interval, 1.26-3.19) or 3.01 (95% confidence interval, 1.81-4.99), respectively, for women with the highest tertile of IGF-I or IGFBP-3 compared with those with the lowest tertile of these molecules. These associations were more evident in premenopausal women or women with high body mass index or high waist-to-hip ratio. No significant association was found for IGF-II. The study confirms that high circulating levels of IGF-I are associated with elevated risk of breast cancer. In contrast to the findings from several studies conducted in Caucasian women, we found that IGFBP-3 was positively associated with breast cancer risk in Chinese women.     

Production of insulin-like growth factor-binding proteins by human central nervous system tumors.

Central nervous system (CNS) tumor cells possess specific receptors for insulin-like growth factors (IGFs) and respond to the growth-promoting effects of IGFs in cell culture. In the present study, we asked whether CNS tumors also produce IGF-binding proteins (BPs) which may modulate the effects of IGFs on CNS tumor cells. Primary cell cultures were established from 20 CNS tumors. Dot blot analysis with 125I-labeled recombinant human IGF-I revealed IGF-binding activity in serum-free conditioned medium from 5 of 7 meningiomas, 7 of 8 malignant gliomas, and 3 of 5 other CNS tumors. Specific IGF BPs in conditioned medium were characterized further by Western ligand and immunoblotting, affinity labeling, and precipitation with specific antibodies against human IGFBP-1, -2, and -3. All conditioned media tested contained an Mr 35,000 BP which was recognized by antiserum against IGFBP-2 and an Mr 24,000 BP that was not recognized by available antisera. Medium conditioned by meningiomas (and one glioma) also contained Mr 45,000 and 50,000 IGF BPs, similar in size and/or immunological properties to growth hormone-dependent BPs present in normal human serum (IGFBP-3). Ligand blotting also showed that meningiomas produce an Mr 29,000 BP; immunoblotting and immunoprecipitation of affinity-labeled IGF-BP complexes confirmed that this BP is recognized by antiserum against IGFBP-1. Immunohistochemistry with specific monoclonal antibodies demonstrated that IGFBP-1 is abundant in pathological specimens of meningiomas and that lower amounts also are detected in malignant gliomas. We conclude that human CNS tumor cells produce a variety of IGF BPs in cell culture, including several that are similar in size and immunological properties to previously characterized human IGF BPs. Immunohistochemistry with specific monoclonal antibodies against IGFBP-1 confirms that this BP is present in vivo, further supporting the concept that IGF BPs may contribute to the regulation of growth in human CNS tumors.     

A prospective study of insulin-like growth factor-I, IGF-binding proteins-1, -2 and -3 and lung cancer risk in women

Insulin-like growth factor-I (IGF-I) has mitogenic and anti-apoptotic properties and has been implicated in the development of breast, colorectum, prostate and lung cancer. IGF binding proteins (IGFBPs) are not only carrier proteins for IGFs but also hold a central position in IGF ligand-receptor interactions through influences on the bioavailability and distribution of IGFs in the extracellular environment. A case-control study nested within the New York University Women's Health Study Cohort included 93 women diagnosed with lung cancer at least 6 months after recruitment into the study. Two controls (n = 186) were matched to each case on age, date of blood sampling, menopausal status, day of menstrual cycle and questionnaire data of smoking status at the time of blood donation. Serum IGF-I, IGFBP-1, -2 and -3, insulin and cotinine were measured. Mean serum levels of IGF-I, IGFBP-1, -2 and -3 were not significantly different between the case and control groups. Univariate logistic regression analyses showed no association of lung cancer risk with serum levels of IGF-I or any of the IGFBPs. These results remained virtually the same in multivariate analyses, including adjustment for cotinine, time since last meal, BMI, IGF-I or IGFBP-3, respectively. Exclusion of cases diagnosed within 3 years of recruitment in the cohort, or restriction of the analyses to adenocarcinomas only, did not alter these results. Our study does not offer evidence in support of an association between prediagnostic serum levels of IGF-I or IGFBP-1, -2 and -3 and lung cancer risk in women.     

Regression of DMBA-induced breast carcinoma following ovariectomy is associated with increased expression of genes encoding insulin-like growth factor binding proteins

Insulin-like growth factor I (IGF-I) has well characterized mitogenic and antiapoptotic effects in both normal and neoplastic mammary epithelial cells which are mediated through the IGF-I receptor. IGF activity is modulated by a family of high affinity IGF binding proteins (IGFBPs 1-6). Here we show that gene expression of IGFBP-2, -3, -4 and -5 increases rapidly in DMBA-induced rat mammary tumors following ovariectomy. We observed a 90% reduction in volume of DMBA-induced rat mammary tumors by 14 days post-ovariectomy. The time course of maximal tumor regression was associated with increased gene expression of IGFBPs, as detected by Northern blot analysis. IGFBP-2, -3, -4 and -5 mRNA levels increased from 2- to 16-fold of control by 14 days of estrogen-ablation. These results are compatible with the hypothesis that response of DMBA-induced mammary tumors to estrogen deprivation therapies involves reduction of IGF bioactivity secondary to upregulation of expression of IGF binding proteins.     

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors.

Insulin-like growth factors (IGFs) play key roles in cell proliferation and apoptosis. Whereas relatively stable within individuals, IGFs vary substantially between individuals, and a large component of this variation may be determined by genetic factors. Several polymorphisms in IGF genes have been identified, although their functional significance is not clear. We evaluated the association of polymorphisms in IGF-1 and IGFBP-3 and circulating levels of IGF-1 and IGFBP-3 in 323 population-based control subjects enrolled in a case-control study of colorectal cancer from September 1999 through February 2002. Total IGF-1 and IGFBP-3 levels were measured using ELISA assays, and all subjects were genotyped for a microsatellite polymorphism in IGF-1 and a single nucleotide polymorphism in IGFBP-3. Multiple linear regression was used to assess the association of genotype with circulating IGFs. IGF-1 levels were unrelated to either polymorphism. IGFBP-3 was significantly associated with IGFBP-3 genotype, with IGFBP-3 levels increasing from CC (1,895 ng/mL) --> GC (2,029 ng/mL) --> GG (2,182 ng/mL), (p-trend < 0.001). Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). Furthermore, both IGF-1 and IGFBP-3 genotypes modified the relationship between postmenopausal hormone use and IGFs. This analysis provides evidence that common variation in IGF genes may contribute to the variation in circulating levels observed between individuals.     

Overexpression of insulin-like growth factor binding protein 4 (IGFBP-4) in MCF-7 breast cancer cells is associated with reduced responsiveness to insulin-like growth factors in vitro and reduced tumour growth in vivo

Insulin-like growth factors (IGF-I and IGF-II) are potent mitogens for breast cancer cells. IGF bioactivity is influenced by IGF binding proteins (IGFBPs). In vitro, most breast cancer cell lines express and secrete IGFBP-4. Sense and antisense complementary DMA of human IGFBP-4 were ligated into a mammalian expression vector and transfected into MCF-7 cells in order to investigate the role of IGFBP-4 on breast cancer cell proliferation in vitro and in vivo. IGFBP-4 concentrations were 4-8-fold higher in conditioned media (CM) of sense IGFBP-4 transfected cells compared to control cells, while IGFBP-4 concentrations in the CM of antisense IGFBP-4 transfected cells were lower than those present in the CM of control cells. Basal growth of sense IGFBP-4 transfected cells (S11) in media supplemented with 0.5% fetal bovine serum was significantly lower (P<0.01) than that of a vector-transfected control (C13) and antisense IGFBP-4 transfected cells (AS4). Loss of IGF but not EGF responsiveness in S11 cells was observed 48 h after exposure to these mitogens. Equal response to Des (1-3) IGF-I (an IGF-I analogue with reduced affinity for IGF binding proteins) was observed for C13, S11 and AS4 cells, suggesting that loss of responsiveness to IGFs by S11 cells is a consequence of IGFBP-4 expression. The in viva proliferation of S11 was significantly (P<0.01) less than that of control C13 and AS4 cells in both lit/lit (IGF-I deficient) or lit/+ (IGF-I replete) hosts. These data demonstrate that IGFBP-4 expression influences breast cancer behaviour.     

High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma

Insulin-like growth factor binding protein-3 (IGFBP-3) modulates cell proliferation of various cancer cell types. However, it remains unclear how IGF-IGFBP-3-signaling is involved in growth and progression of hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the role of IGFBP-3 in HCC. Type 1 receptor for IGF (IGF-1R) was expressed at various levels in the seven lines examined, but IGF-2R was not expressed. Of the seven lines, the growth of HAK-1B, KIM-1, KYN-2 and HepG2 cells was stimulated in a dose-dependent manner by the exogenous addition of IGF-I or IGF-II, but the HAK-1A, KYN-1 and KYN-3 cell lines showed no growth. Exogenous addition of IGFBP-3 markedly blocked IGF-I and IGF-II-stimulated cell growth of KYN-2 and HepG2 cells, and moderately stimulated that of KIM-1 and HAK-1B cells, but no growth of the KYN-1, KYN-3 and HAK-1A cell lines was observed. IGF-I enhanced the phosphorylation of IGF-1R, Akt and Erk1/2 in KYN-2 cells, and coadministration of IGFBP-3 blocked all types of activation by IGF-I investigated here. In contrast, no such activation by IGF-I was detected in KYN-3 cells. IGFBP-3 also suppressed IGF-I-induced cell invasion by KYN-2 cells. Moreover, we were able to observe the apparent expression of IGFBP-3 in KYN-3 cells, but not in the other six cell lines. Furthermore reduced expression of IGFBP-3, but not that of IGF-1R, was significantly correlated with tumor size, histological differentiation, capsular invasion and portal venous invasion. Low expression of IGFBP-3 was independently associated with poor survival. IGFBP-3 could be a molecular target of intrinsic importance for further development of novel therapeutic strategy against HCC.     

Igf-independent regulation of breast cancer growth by IGF binding proteins

The human IGFBP family consists of at least seven proteins, designated as IGFBP-1, -2, -3, -4, -5, -6, and-7. IGFBPs 1-6 bind IGF-I and IGF-II with high affinity whereas IGFBP-7, a newly identified IGFBP, binds IGFs with lower affinity and constitutes a low-affinity member of the IGFBP family. IGFBPs serve to transport the IGFs, prolong their half-lives, and modulate their biological action. At the cellular level, IGFBPs can either potentiate or inhibit the mitogenic effects of IGFs, depending upon cell types and IGFBP species (IGF-dependent action of IGFBPs). However, recent studies have indicated that IGFBPs, especially IGFBP-3, potently inhibit breast cancer cell growth in an IGF-independent manner. The IGF-independent action of IGFBP-3 requires interaction with cell-surface association proteins, presumably putative IGFBP-3 specific receptors, and is responsible for growth inhibitory action of the known growth suppressing factors such as TGF-, retinoic acid, and antiestrogens in breast cancer cells. Thus, IGFBP-3 appears to be a major factor in a negative control system involved in regulating human breast cancer cell growth in vitro. IGFBP-7, representing a low affinity IGFBP, appears to function as an IGF-independent cell growth regulator in breast cancer cells. Overall structural similarity between IGFBP-7 and classical high affinity IGFBPs 1-6 suggests that the mechanisms of action and signaling pathways used by IGFBP-7 may provide insight into the IGF-independent actions of the high affinity IGFBPs.A fuller understanding of the IGF-independent action of IGFBPs will allow us to understand how the growth of neoplastic cells can be modulated by the IGF/IGFBP system, and how other growth factors or pharmacological agents can interface with this system.     

Mitogenic Properties of Insulin-Like Growth Factors I and II, Insulin-like Growth Factor Binding Protein-3 and Epidermal Growth Factor on Human Breast Stromal Cells in Primary Culture

Insulin-like growth factors I and II (IGF-I and IGF-II) are growth factors implicated in both normal mammary gland development and breast cancer. We have previously reported on the effects of components of the IGF system on breast epithelial cells. Since data suggests that stromal-epithelial interactions play a crucial role in breast cancer, we have now investigated the mitogenic properties of IGF-I, IGF-II, insulin-like growth factor binding protein-3 (IGFBP-3) and epidermal growth factor (EGF) on human breast stromal cells in primary culture. We show that, under serum-free conditions, stromal cells are stimulated to grow in response to IGF-I and IGF-II in a dose-dependent manner. IGF-I and EGF, a potent stimulator of human breast epithelial cell growth in primary culture and also associated with breast cancer, appear to stimulate stromal cell growth in a synergistic manner. IGFBP-3 does not inhibit the stimulation of growth by IGF-I, or IGF-I plus EGF. However, IGFBP-3 does inhibit the stimulation of growth by IGF-II. In contrast to our previous results with human breast epithelial cells, IGFBP-3 does not have an IGF-independent inhibitory effect on stromal cell growth. This study is the first to address the effects of IGF-I, IGF-II and IGFBP-3 alone and in combination with EGF on human breast stromal cell growth in primary culture. Characterizing the role of the IGF system in both normal breast epithelial cells and stromal cells will aid in our understanding of the mechanisms behind the role of the IGF system in breast cancer.     

Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers.

We have compared the expression of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ten paired samples of normal and tumour colonic tissue with regard to both mRNA and protein. We have compared sensitivity of these tissues to IGF-I using primary cultures of epithelial cells of colonic mucosa, and we have examined the production of IGFs and IGFBPs by these cells. In the tissues, IGFBP-2 mRNA was expressed in all normal and cancer samples but other IGFBPs showed variable expression. mRNAs for IGF-I were expressed in all normal and cancer tissues but IGF-II mRNA was only detected in cancer tissue (3 out of 10). Immunostaining of sections of normal and cancer tissue was negative for IGF-I and IGF-II; IGFBP-2 was positive in 2 out of 10 cancer tissues and 7 out of 10 normal tissues; IGFBP-3 was positive in 7 out of 10 cancer tissues and 7 out of 10 normal tissues; and IGFBP-4 was positive in 5 out of 10 cancer tissues and 6 out of 10 normal tissues. In the cells in culture, cancer cells showed increased incorporation of [35S]methionine into protein and [3H]thymidine into DNA (P < 0.02) when treated with IGF-I. Western blotting of serum-free conditioned media from cells in culture showed that 8 out of 10 normal and 3 out of 10 cancer cultures produced a 32-kDa immunoreactive IGFBP-2. No IGFBP-3 was secreted by any culture but 24-kDa IGFBP-4 was found in 3 out of 10 normal and 5 out of 10 cancer tissues. Because of the discrepancy between mRNA and protein expression for IGFBP-2, degradation of native IGFBPs was assessed using tissue extracts. Colon cancer extracts were able to degrade exogenous IGFBP-2, IGFBP-3 and IGFBP-4, whereas normal tissue extracts were without effect on IGFBP-2. We conclude that IGFBPs are synthesized and secreted by cells of the colonic mucosa but that proteolysis of secreted IGFBP-2 occurs in colon cancer tissue. This selective degradation may confer a growth advantage.     

Insulin-like growth factors and prostate cancer: a population-based case-control study in China.

Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate epithelial cells. Through modulation of IGF bioactivity and other mechanisms, IGF-binding proteins (IGFBPs) also have growth-regulatory effects on prostate cells. Recently, IGF-I and IGFBP-3 have been implicated in prostate cancer risk among Western populations. To assess whether IGF-I, IGF-II, IGFBP-1, or IGFBP-3 are also associated with prostate cancer in a low-risk population, we measured plasma levels of these factors among 128 newly diagnosed prostate cancer cases and 306 randomly selected population controls in Shanghai, China. Relative to the lowest quartile of IGF-I levels, men in the highest quartile had a 2.6-fold higher prostate cancer risk, with a significant trend [odds ratio (OR) = 2.63; 95% confidence interval (95% CI) = 1.19-5.79; P(trend) = 0.01]. In contrast, men in the highest quartile of IGFBP-3 levels had a 46% decreased risk relative to the lowest quartile (OR = 0.54; 95% CI = 0.26-1.15; P(trend) = 0.08). A similar but less distinct result was observed for IGFBP-1 (OR = 0.60; 95% CI = 0.31-1.17; P(trend) = 0.25). Men in the highest quartile for the IGF-I:IGFBP-3 molar ratio (an indirect measure of free IGF-I) had a 2.5-fold higher risk compared with the lowest quartile (OR = 2.51; 95% CI = 1.32-4.75, P(trend) < 0.001). These associations were more pronounced after adjustment for serum 5alpha-androstane-3alpha,17beta-diol glucuronide and sex hormone-binding globulin levels. There was no significant association with IGF-II levels. Our findings in a low-risk population provide evidence that IGF-I, IGFBP-3, and IGFBP-1 are determinants of prostate cancer and indicate that additional studies are needed to evaluate their effects on ethnic and geographic incidence differentials and to elucidate carcinogenic mechanisms.     

Joint effect of insulin-like growth factors and sex steroids on breast cancer risk.

Insulin-like growth factors (IGFs) and estrogens are essential hormones regulating the growth and differentiation of mammary cells. Studies have shown that IGFs and estrogens are strong mitogens for breast cancer cells and that high circulating IGF-I and estrogens are risk factors of breast cancer. Laboratory experiments further indicate that these hormones act synergistically on the pathogenesis of breast cancer. Estrogens increase the effect of IGF-I on breast cancer cells by stimulating the expression of IGF-I and IGF-I receptor; IGFs enhance the action of estrogens by regulating the production of estrogen receptor. Furthermore, the two systems have substantial signal transduction cross-talk. Despite the laboratory indications, there is no epidemiological evidence in support of the joint effect of IGFs and estrogens on breast cancer risk. To test this hypothesis in human populations, we compared plasma levels of IGFs and sex steroid hormones among 300 incident breast cancer patients and 300 age- and menopause-matched control women derived from a large population-based case-control study conducted in Shanghai, China between 1996 and 1998. Fasting morning blood samples were measured for plasma concentrations of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, estradiol, estrone, estrone sulfate, testosterone, and dehydroepiandrosterone sulfate using commercial immunoassay kits. Levels of these hormones were classified into two groups based on the median levels in the control group and combined between IGFs and steroid hormones. Conditional logistic regression analysis was performed to examine the association of breast cancer risk with the combined variables of sex steroids and IGFs. A synergistic effect on breast cancer risk was suggested for IGF-I or IGFBP-3 with estrone or testosterone among both pre- and postmenopausal women. Compared with premenopausal women with low circulating levels of both IGF-I and estrone, the odds ratios were 1.21 [95% confidence interval (CI), 0.61-2.40] for high estrone, 1.50 (95% CI, 0.77-2.93) for high IGF-I, and 2.30 (95% CI, 1.21-4.37) for both high estrone and high IGF-I. Similar patterns of association were also seen for IGF-I with testosterone as well as for IGFBP-3 with estrone or testosterone, and some of the interactions were statistically significant or borderline significant (P < 0.10). No joint effects were found for IGF-I or IGFBP-3 with estradiol or estrone sulfate. In conclusion, the study suggests a possible synergy between IGF peptide hormone and sex steroid hormones, including both estrogen and androgen, in relation to breast cancer risk.