Papers by Antonino Belfiore
Oncotarget, Jan 10, 2015
We recently established a critical role for the growth factor progranulin in bladder cancer insof... more We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition...
Insulin-like Growth Factors and Cancer, 2011
ABSTRACT Dysregulation of the insulin growth factor (IGF) system is implicated in various aspects... more ABSTRACT Dysregulation of the insulin growth factor (IGF) system is implicated in various aspects of cancer. Notably, the physiological signaling specificity existing between insulin and insulin-like growth factors I and II (IGFs) is often disrupted in cancer by various mechanisms. These may include overexpression of IGFs and of IGF-I receptors (IGF-IR), aberrant expression of insulin receptor isoform A, and appearance of atypical receptors that bind both insulin and IGFs. Enhanced cross talk between insulin and the IGF-I receptors may also result from insulin resistance and chronic hyperinsulinemia, newly recognized risk factors for cancer. All these factors associated with reduced signaling specificity between insulin and IGFs may also activate unbalanced intracellular signaling more strongly coupled to protumoral biological effects than to metabolic effects. A better knowledge of the molecular mechanisms involved may have profound implications in cancer prevention and therapy.
Insulin Resistance and Cancer, 2011
Page 1. 243 IG Fantus (ed.), Insulin Resistance and Cancer: Epidemiology, Cellular and Molecular ... more Page 1. 243 IG Fantus (ed.), Insulin Resistance and Cancer: Epidemiology, Cellular and Molecular Mechanisms and Clinical Implications, Energy Balance and Cancer 1, DOI 10.1007/978-1-4419-9911-5_11, © Springer Science+Business Media, LLC 2011 Introduction ...
Growth Hormone & IGF Research, 2014
Oncotarget, Jan 28, 2015
The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian deve... more The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological ...
Frontiers in endocrinology, 2014
Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, c... more Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth, and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT) and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the e...
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting, 2012
Increased signaling of the insulin-like growth factor (IGF) system via alterations in expression ... more Increased signaling of the insulin-like growth factor (IGF) system via alterations in expression levels of its components has been demonstrated in various tumor types. Numerous experimental studies have supported the involvement of the IGF system signaling axis in tumor initiation and progression. These studies, combined with data that link alterations in the levels of circulating IGFs with cancer risk and prognosis, have focused on the IGF-1 receptor (IGF-1R) as a therapeutic target for patients with cancer. As a consequence, most therapeutic strategies have been designed to specifically inhibit IGF-1R but have for the most part ignored the insulin receptor (IR), based on concerns that targeting IR would lead to unacceptable toxicity both because of its role in physiologic metabolism and because we frequently try to oversimplify biologic complexity whenever we are urged to find practical, friendly solutions for clinical practice. Although this is an understandable and necessary sta...
Frontiers in endocrinology, 2013
Minerva endocrinologica, 2012
Thyroid cancer is the most common endocrine malignancy. Although the majority of thyroid cancers ... more Thyroid cancer is the most common endocrine malignancy. Although the majority of thyroid cancers are well differentiated and have a favorable prognosis, a minor proportion are poorly differentiated malignancies, which show an aggressive behavior and are refractory to conventional cancer treatments. The molecular mechanisms underlying thyroid development and progression are incompletely understood. Most of thyroid tumorigenesis models propose that thyroid cancer originates from the normal thyrocytes that, via the accumulation of genetic alterations, acquire a malignant phenotype and the ability to metastatize. However, recent progress in clarifying the molecular mechanisms of thyroid embryogenesis/development and the discovery of fetal/stem-like cells within the thyroid gland, have raised the possibility that thyroid cancer originates from progenitor/stem cells. These cells have the ability to self-renew and to undergo multilineage differentiation, and are resistant to common antican...
Frontiers in Endocrinology, 2015
The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated level... more The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as transcription factors; however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/G-protein estrogen receptor (GPER), is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs). In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression.
Molecular and cellular biology, 1999
Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insu... more Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin l...
Cancer research, 1994
TTF-1 and PAX-8 are tissue-specific transcription factors expressed in the thyroid follicular cel... more TTF-1 and PAX-8 are tissue-specific transcription factors expressed in the thyroid follicular cells, contributing to the maintenance of the differentiated phenotype. In fact, it has been demonstrated that TTF-1 and PAX-8 are able to activate transcription from thyroglobulin and thyroperoxidase (TPO) promoters, the transcriptional activity of which is in vivo restricted only to the thyroid follicular cell. In order to gain insight into how these transcription factors control in vivo the differentiation of the thyroid cell and to have a better molecular characterization of human thyroid tumors, TTF-1, PAX-8, thyroglobulin, and TPO mRNA levels were measured in nonmalignant and malignant human thyroid tissues. Results indicate that the expression of TTF-1 and PAX-8 is not sufficient per se for the expression of the thyroid-differentiated phenotype. Furthermore, in follicular adenomas, PAX-8 mRNA levels are strictly related to TPO mRNA levels, suggesting that the amount of PAX-8 could pl...
Giornale italiano di oncologia
The Authors have evaluated the relationship between the presence of estrogen (ER) and progesteron... more The Authors have evaluated the relationship between the presence of estrogen (ER) and progesterone (PgR) receptors and the ovarian function in 321 consecutive and unselected women who have undergone surgery for breast cancer. A significant relationship was found between the presence and the concentration of steroid receptors (ER and PgR) in the neoplastic tissue and the ovarian function. The Authors confirm the importance of considering the menopausal status in the evaluation of the results of steroid receptor assay.
Cancer research, Jan 15, 1992
We have previously reported that insulin receptor expression is increased in human breast cancer ... more We have previously reported that insulin receptor expression is increased in human breast cancer specimens (V. Papa et al., J. Clin. Invest., 85:1503-1510, 1990). In the present study, in order to further understand the role of the insulin receptor in breast cancer, insulin receptor expression and function were characterized in three human breast cancer cell lines, MCF-7, ZR-75-1, and T-47D, and compared to a nonmalignant human breast epithelial cell line, 184B5. Insulin receptor content, measured by radioimmunoassay, was elevated 5- and 3-fold in MCF-7 and ZR-75-1 breast cancer cell lines, respectively, when compared to the nonmalignant cell line 184B5. In contrast, the insulin receptor content of T-47D cells was not increased. The increase in insulin receptor content in MCF-7 and ZR-75-1 cells was not due to amplification of the insulin receptor gene. Also, total insulin receptor mRNA content was not increased in breast cancer cells in respect to nonmalignantly transformed 184B5 b...
Oncogene, 1992
The receptor for Hepatocyte Growth Factor is a transmembrane tyrosine kinase encoded by the c-MET... more The receptor for Hepatocyte Growth Factor is a transmembrane tyrosine kinase encoded by the c-MET oncogene. We have previously shown that the Met protein is expressed in several human epithelial tissues. The receptor is barely detectable, however, in normal thyroids and in specimens from patients affected by non-neoplastic thyroid diseases. Now we report that the expression of the Met/HGF receptor is increased a hundred fold in 22 out of 41 human carcinomas derived from the thyroid follicular epithelium. A comprehensive analysis of 15 cases showed that the overexpressing carcinomas belong to histotype variants correlated with negative prognosis and in all but one case there were evidences of locally advanced disease and/or distant metastases. The 11 benign adenomas and the 5 medullary carcinomas tested were negative. Western blot analysis with monoclonal antibodies directed against either the intracellular or the extracellular receptor domains failed to reveal major structural alter...
Journal of Oncology, 2012
Endocrine cancers are a heterogeneous group of diseases that may arise from endocrine cells in an... more Endocrine cancers are a heterogeneous group of diseases that may arise from endocrine cells in any gland of the endocrine system. These malignancies may show an aggressive behavior and resistance to the common anticancer therapies. The etiopathogenesis of these tumors remains mostly unknown. The normal embryological development and differentiation of several endocrine glands are regulated by specific pituitary tropins, which, in adult life, control the function and trophism of the endocrine gland. Pituitary tropins act in concert with peptide growth factors, including the insulin-like growth factors (IGFs), which are considered key regulators of cell growth, proliferation, and apoptosis. While pituitary TSH is regarded as tumor-promoting factor for metastatic thyroid cancer, the role of other pituitary hormones in endocrine cancers is uncertain. However, multiple molecular abnormalities of the IGF system frequently occur in endocrine cancers and may have a role in tumorigenesis as well as in tumor progression and resistance to therapies. Herein, we will review studies indicating a role of IGF system dysregulation in endocrine cancers and will discuss the possible implications of these findings for tumor prevention and treatment, with a major focus on cancers from the thyroid, adrenal, and ovary, which are the most extensively studied.
The Journal of Headache and Pain, 2008
The pathophysiology of pituitary-associated headache is unknown, although structural and function... more The pathophysiology of pituitary-associated headache is unknown, although structural and functional features of the tumour are proposed mechanisms. The objective of this study was to evaluate whether headache in a population with pituitary micro-adenomas was related to hyperprolactinemia. We recruited 29 patients with microprolactinoma and headache: 16 with migraine (group A) and 13 with tension-type-headache (group B). The prolactin (PRL) levels measured during attacks of headache were significantly higher in nine patients (56%) of group A and in one patient (8%) of group B. In four of the nine patients of group A, PRL increased after thyrotropinreleasing-hormone (TRH) test and induced severe attacks. After dopamine-agonist (DA) treatment, the headache improved in seven (44%) patients of the group A and in two (15%) patients of the group B. Three of the four patients in whom the TRH-test induced headache attacks, improved after DA treatment. We suggest that hyperprolactinemia may contribute to development of pain in migraine subgroups and further TRH-test could be used to predict which patients could benefit by DA therapy.
International Journal of Obesity, 2010
Objective: We aimed at evaluating whether the addition of low-dose metformin to dietary treatment... more Objective: We aimed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD). Methods: We carried out a 6-month prospective study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis. In total, 50 patients were enrolled and randomized into two groups: the first group (n ¼ 25) was given metformin (1 g per day) plus dietary treatment and the second group (n ¼ 25) was given dietary treatment alone. Results: At the end of the study, the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin (Po0.0001) and the diet group (P ¼ 0.029). Moreover, patient body mass index and waist circumference significantly decreased in both groups (Po0.001). Fasting glucose, insulin resistance (evaluated as homeostasis model assessment of insulin resistance (HOMA-IR)) and serum adiponectin decreased in both groups, although these changes reached statistical significance only in the metformin group. In this group, HOMA-IR decreased from 3.3±1.6 to 2.4±1.2 (P ¼ 0.003), whereas it decreased from 3.2 ± 1.6 to 2.8 ± 1.1 (not significant, NS) in the diet group. Similarly, the proportion of patients with impaired fasting glucose declined from 35 to 5% (P ¼ 0.04) in the metformin and from 32 to 12% (NS) in the diet group. At baseline, B40% of patients in both groups met the diagnostic criteria of metabolic syndrome. This proportion decreased to 20% in the metformin group (P ¼ 0.008) and to 32% in the diet group (NS). Conclusions: In our 6-month prospective study, both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD. However, metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients.
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Papers by Antonino Belfiore