Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy.

The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IR) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth.

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals.

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells.

Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR axis in malignant mesothelioma.

Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both EphrinB2 ligand-dependent and independent mechanisms.

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny.

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied.

The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides.

Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce an increase in brain-derived neurotrophic factor (BDNF) expression. Cu ions played a critical role in the modulation of the biological activity of NGF(1-14).

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type-1 insulin-like growth factor receptors in neuronal cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β-amyloid (Aβ), and neuronal loss. The self-association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem.

Chromosome 15 structural abnormalities: effect on gene expression and function.

Insulin-like growth factor 1 receptor (), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the gene expression and function in three unrelated patients with chromosome 15 structural abnormalities.

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor.

The nerve growth factor (NGF) N-terminus peptide, NGF(1-14), and its acetylated form, Ac-NGF(1-14), were investigated to scrutinize the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor by both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1-14) by the domain 5 of TrkA (TrkA-D5).

Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons.

ß-amyloid (Aß1-42) is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1-42self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer's disease (AD). However, Aß1-42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1-42 in neuronal function is largely unknown.

Insulin has multiple antiamyloidogenic effects on human neuronal cells.

Alzheimer's disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mechanism is not clear. We analyzed the effect of insulin on several molecular steps of amyloid precursor protein (APP) processing and β-amyloid (Aβ) intracellular accumulation in a panel of human neuronal cells and in human embryonic kidney 293 cells overexpressing APP-695.

Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway.

Proinsulin is generally regarded as an inactive prohormone because of its low metabolic activity. However, proinsulin appears to regulate embryo development in animal models. In this study, we evaluated whether proinsulin may differentially bind to and activate the two insulin receptor (IR) isoforms (IR-A and IR-B), because IR-A is a relatively low-specificity receptor that is prevalent in fetal and cancer cells and is able to mediate the growth effects of IGF-II.

Research resource: New and diverse substrates for the insulin receptor isoform A revealed by quantitative proteomics after stimulation with IGF-II or insulin.

The isoform A of the insulin receptor (IR) (IR-A) is a bifunctional receptor, because it binds both insulin and IGF-II. IR-A activation by IGF-II plays a role in development, but its physiological role in adults is unknown. IGF-II signaling through IR-A is deregulated in cancer and favors tumor progression.

Reactivation of p53 mutants by prima-1 [corrected] in thyroid cancer cells.

Most undifferentiated thyroid carcinomas express p53 mutants and thereafter, are very resistant to chemotherapy. p53 reactivation and induction of massive apoptosis (Prima-1) is a compound restoring the tumor-suppressor activity of p53 mutants. We tested the effect of Prima-1 in thyroid cancer cells harboring p53 mutations.

Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid.

Context: Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR).

Objective: We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant.

Palmitate affects insulin receptor phosphorylation and intracellular insulin signal in a pancreatic alpha-cell line.

This study investigated in a pancreatic alpha-cell line the effects of chronic exposure to palmitate on the insulin and IGF-I receptor (IGF-IR) and intracellular insulin pathways. alpha-TC1-6 cells were cultured in the presence or absence of palmitate (0.5 mmol/liter) up to 48 h.

HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene.

The IGF-I receptor (IGF-IR) is often overexpressed in cancer and is believed to play a crucial role in cancer progression. High Mobility Group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate gene expression through DNA binding and involvement in enhanceosome complexes. HMGA1 is expressed at low level in adult differentiated cells, whereas it is expressed at high level in embryonic and malignant cells.

Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B).

Role of cyclic AMP response element-binding protein in insulin-like growth factor-i receptor up-regulation by sex steroids in prostate cancer cells.

Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element-binding protein (CREB) activation.

Diabetes and cancer.

Diabetes and cancer are two heterogeneous, multifactorial, severe, and chronic diseases. Because of their frequency, reciprocal influences - even minor influences - may have a major impact. Epidemiological studies clearly indicate that the risk of several types of cancer (including pancreas, liver, breast, colorectal, urinary tract, and female reproductive organs) is increased in diabetic patients.

Differential signaling activation by insulin and insulin-like growth factors I and II upon binding to insulin receptor isoform A.

A variety of human malignancies overexpresses isoform A of the insulin receptor (IR-A) and produces IGFs (IGF-I and/or IGF-II). IR-A binds IGF-II with high affinity (although 4-fold lower than that for insulin), whereas it binds IGF-I with low affinity (approximately 30-fold lower than that for insulin). However, in engineered cells expressing only the IR-A, but not IGF-I receptor (R(-)/IR-A cells), IGF-II is a more potent mitogen than insulin.

c-Abl and insulin receptor signalling.

Insulin Receptor (IR) and IGF-I receptor (IGF-IR) are homolog but display distinct functions: IR is mainly metabolic, while IGF-IR is mitogenic. However, in some conditions like foetal growth, cancer and diabetes, IR may display some non-metabolic effects like proliferation and migration. The molecular mechanisms underlying this 'functional switch of IR' have been attributed to several factors including overexpression of ligands and receptors, predominant IR isoform expression, preferential recruitment of intracellular substrates.

Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway.

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors.

The role of insulin receptors and IGF-I receptors in cancer and other diseases.

There is evidence, both in vitro and in vivo, that receptor tyrosine kinases play a key role in the formation and progression of human cancer. In particular, the insulin-like growth factor receptor (IGF-IR), a tyrosine kinase receptor for IGF-I and IGF-II, has been well documented in cell culture, animal studies, and humans to play a role in malignant transformation, progression, protection from apoptosis, and metastasis. In addition, the hormone insulin (which is very closely related to the IGFs) and its tyrosine kinase receptor (the IR, which is very closely related to the IGR-IR) have been documented both in vitro and in vivo to play a key role in cancer biology.

TAp73 alpha increases p53 tumor suppressor activity in thyroid cancer cells via the inhibition of Mdm2-mediated degradation.

p53 family proteins include p53 tumor suppressor, p63, and p73. Despite the high similarity in structure and function with p53, p63, and p73 function in tumor suppression is still controversial. Here, we show that TAp73alpha, a transcriptionally active p73 isoform, is able to synergize p53 tumor suppressor function in thyroid cancer cells.