Fetal Insulin Receptors Research Articles

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 (IRA) 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. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers.

The Emerging Role of the Fetal Insulin Receptor in Hormone-refractory Breast Cancer.

Type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor and a mediator of the biologic effects of insulin-like growth factor (IGF)-I and -II. Inhibitors of IGF-1R signaling were tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target; essentially all IGF-1R inhibitors failed to provide an additional benefit compared with standard-of-care therapy. In this review, we will evaluate the role the insulin receptor (IR) plays in mediating IGF signaling and subsequent metabolic and mitogenic effects as 1 possible reason for these failures. IR is expressed as 2 isoforms, with the fetal isoform IR-A derived from alternative splicing and loss of exon 11, the adult isoform (IR-B) includes this exon. Cancer frequently re-expresses fetal proteins and this appears to be the case in cancer with a re-expression of the fetal isoform and an increased IR-A:IR-B ratio. The biological effects of IR isoform signaling are complex and not completely understood although it has been suggested that IR-A could stimulate mitogenic signaling pathways, play a role in cancer cell stemness, and mediate tolerance to cancer therapies. From a clinical perspective, the IR-A overexpression in cancer may explain why targeting IGF-1R alone was not successful. However, given the predominance of IR-A expression in cancer, it may also be possible to develop isoform specific inhibitors and avoid the metabolic consequences of inhibiting IR-B. If such inhibitors could be developed, then IR-A expression could serve as a predictive biomarker, and cotargeting IR-A and IGF-1R could provide a novel, more effective therapy method.

IGF‐II Binding to Insulin Receptor Isoform A Induces a Partially Different Gene Expression Profile from Insulin Binding

Insulin receptor isoform A (IR-A) is a fetal insulin receptor isoform that is overexpressed in cancer. We investigated whether insulin-like growth factor (IGF)-II may elicit a different gene expression response from insulin in cells expressing only IR-A and lacking IGF-I receptor (R-/IR-A cells). Cells were stimulated with either insulin or IGF-II (at 0.5, 3, and 8 h), and global gene expression was studied by microarray technology. Results were validated by quantitative real-time PCR. We found that 214 transcripts were similarly regulated by insulin and IGF-II, whereas 45 transcripts were differentially regulated. Of these 45 genes, 18 were responsive to only one of the two ligands (12 to insulin and 6 to IGF-II). Twenty-seven transcripts were regulated by both ligands but with a significant difference at at least one time point. IGF-II was a more potent regulator than insulin for these genes. In conclusion, insulin and IGF-II, acting via the same receptor (IR-A), may differentially affect gene expression in cells. These findings provide a molecular basis in clarifying the biological role of IR-A in embryonic/fetal life and in cancer.

The insulin receptor

Cells are endowed with specific cognitive molecules that function as receptors for hormones, neurotransmitters, and other intercellular messengers. The receptor molecules may be present in the plasma membrane, cytoplasm, or nucleus. When occupied by the messenger, the receptor is coupled to the cellular machinery that responds to the message-bearing molecules. For some hormones the events following attachment of the messenger to the receptor are well known. An example is the generation of cAMP after combination of glucagon with its receptor and the series of steps culminating in activation of phosphorylase. In the case of many other messengers, including insulin, the nature of these coupling steps is not known. Receptors are subject to the regulatory processes of synthesis, degradation, and conformational change; alterations in receptor properties may have significant effects on the qualitative and quantitative responses of the cell to the extracellular messenger. The insulin receptor is located in the plasma membrane, is composed of two pairs of subunits, and has a molecular weight of about 350,000. It is located in cells such as adipocytes, hepatocytes, and skeletal muscle cells as well as in cells not considered to be typical target organ cells. Insulin receptors in nonfetal cells are downregulated by exposure of the cells to high concentrations of insulin. Other factors that regulate insulin binding include muscular exercise, diet, thyroid hormones, glucocorticoids, androgens, estrogens, and cyclic nucleotides. The fetus has high concentrations of insulin receptors in several tissues. These begin to appear early in fetal life and may outnumber those found in adult tissues. Fetal insulin receptors are unusual in that they may not undergo downregulation but may experience the opposite when exposed to insulin in high concentrations. Thus the offspring of a mother with poorly controlled diabetes may be placed in double jeopardy by fetal hyperinsulinemia and augmented insulin binding by the receptors. Many disorders in children and adults are associated with changes in the properties of the insulin receptor. In general, the alterations have been measured in receptor-bearing cells that are readily accessible, such as circulating monocytes and erythrocytes. The receptors on these cells generally reflect the status of receptors on the major target organs of insulin, although exceptions are known, and conclusions drawn from studies of receptors on circulating cells must be made with caution.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased fetal insulin receptors and changes in membrane fluidity and lipid composition.

Fetal tissues exposed to hyperinsulinemia in utero have significantly greater numbers of insulin receptors than do those of controls. We have studied this upregulation phenomenon using crude microsomal membranes from fetal rabbit litters exposed to varying degrees of hyperinsulinemia in diabetic pregnant rabbits. We have observed that insulin binding capacity of membranes increased directly with the severity of maternal diabetes, ranging from 8.5 ng in controls to 44.6 ng insulin/mg membrane protein in offspring of severely diabetic animals and related directly with increasing fetal insulin levels (r = 0.77, P less than 0.005). Lipid analyses of fetal lung membranes showed that reduction of phospholipid to protein ratios occurred in the presence of maternal diabetes. Membrane cholesterol-to-phospholipid ratios were also altered in the presence of maternal diabetes. Significantly, increases in plasma membrane microviscosity were noted in the membranes from diabetic offspring. The data suggest that reduction of membrane fluidity is associated with increases in fetal membrane insulin receptors in severely diabetic pregnancies.

Glucocorticoids and hypothyroidism modulate development of fetal lung insulin receptors.

We investigated the development of insulin receptors in membranes of fetal rabbit lung during normal ontogeny and the effect of glucocorticoids and hypothyroidism. Specific binding of 125I-insulin to fetal lung membranes increased progressively to a peak at 29 days gestation, declining by 30 days. Scatchard plots were curvilinear and revealed a progressive increase in receptor numbers (X 10(10)/mg protein) from 129 +/- 7 (mean +/- SE) at 22-24 days to 575 +/- 16 at 29 days, declining to 467 +/- 12 at 30 days, term being approximately 31 days. Affinities did not change throughout gestation and were similar to those of adult lung; receptor numbers in adults were significantly lower than in fetuses at 26-30 days. Epinephrine and PGE1 could evoke a doubling of cAMP production in adult and fetal lung membranes until 29 days. Concomitantly with the fall in fetal insulin receptor number at 30 days, cAMP production in response to epinephrine or PGE1 increased fivefold. Induction of fetal hypothyroidism decreased insulin receptor numbers in the lung of the 28-day fetus by 70% from control (P less than 0.001) without a change in receptor affinity. In contrast, betamethasone administration increased fetal lung insulin receptor numbers by 250% (P less than 0.001) but did not alter their affinity; maternal lung insulin receptors were not altered. Thus, normal ontogeny of the fetal lung insulin receptor is characterized by a progressive increase in number followed by decline immediately before parturition associated with a sharp increase of cAMP responsiveness of the membranes. Hypothyroidism and glucocorticoid exposure can modulate the normal development of the fetal lung insulin receptor.

The insulin receptor.

Cells are endowed with specific cognitive molecules that function as receptors for hormones, neurotransmitters, and other intercellular messengers. The receptor molecules may be present in the plasma membrane, cytoplasm, or nucleus. When occupied by the messenger, the receptor is coupled to the cellular machinery that responds to the message-bearing molecules. For some hormones the events following attachment of the messenger to the receptor are well known. An example is the generation of cAMP after combination of glucagon with its receptor and the series of steps culminating in activation of phosphorylase. In the case of many other messengers, including insulin, the nature of these coupling steps is not known. Receptors are subject to the regulatory processes of synthesis, degradation, and conformational change; alterations in receptor properties may have significant effects on the qualitative and quantitative responses of the cell to the extracellular messenger. The insulin receptor is located in the plasma membrane, is composed of two pairs of subunits, and has a molecular weight of about 350,000. It is located in cells such as adipocytes, hepatocytes, and skeletal muscle cells as well as in cells not considered to be typical target organ cells. Insulin receptors in nonfetal cells are downregulated by exposure of the cells to high concentrations of insulin. Other factors that regulate insulin binding include muscular exercise, diet, thyroid hormones, glucocorticoids, androgens, estrogens, and cyclic nucleotides. The fetus has high concentrations of insulin receptors in several tissues. These begin to appear early in fetal life and may outnumber those found in adult tissues. Fetal insulin receptors are unusual in that they may not undergo downregulation but may experience the opposite when exposed to insulin in high concentrations. Thus the offspring of a mother with poorly controlled diabetes may be placed in double jeopardy by fetal hyperinsulinemia and augmented insulin binding by the receptors. Many disorders in children and adults are associated with changes in the properties of the insulin receptor. In general, the alterations have been measured in receptor-bearing cells that are readily accessible, such as circulating monocytes and erythrocytes. The receptors on these cells generally reflect the status of receptors on the major target organs of insulin, although exceptions are known, and conclusions drawn from studies of receptors on circulating cells must be made with caution.(ABSTRACT TRUNCATED AT 400 WORDS)