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Growth Hormone in Vascular Pathology: Neovascularization and Expression of Receptors Is Associated with Cellular Proliferation

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Growth Hormone in Vascular Pathology: Neovascularization and Expression of Receptors Is Associated with Cellular Proliferation ANTICANCER RESEARCH 27: 4201-4218 (2007) Growth Hormone in Vascular Pathology: Neovascularization and Expression of Receptors is Associated with Cellular Proliferation D.T. LINCOLN1, P.K. SINGAL2 and A. AL-BANAW3 1Entity Systems, Independent Research Foundation, 53 Ashburton Street, Chapel Hill QLD 4069, Australia; 2Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, Faculty of Medicine, University of Manitoba, Winnipeg, Canada; 3Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, Kuwait Abstract. Vascular tumours are common lesions of the skin contents, duodenum, female breast, abdomen, stomach, colon, and subcutaneous tissue, but also occur in many other tissues lymph node, bladder, body flank and neck regions. The tumours and internal organs. The well-differentiated tumours consist of were of the following pathological entities: Haemangioma irregular anastomosing, blood-filled vascular channels that are (n=12); haemangioendothelioma (n=10); Castleman’s disease lined by variably atypical endothelial cells. The less differentiated (n=3), haemangiopericytoma (n=4); angiosarcoma, (n=11), tumours may show solid strands and sheets, resembling Kaposi’s sarcoma with focal infiltration by lymphoma, HIV +ve carcinoma or lymphoma. Several growth factors, including basic (n=7), Kaposi’s sarcoma (n=17). The endothelial cell marker fibroblast growth factor, transforming growth factors and CD-31 was used to establish endothelial cell characteristics and vascular endothelial growth factor, play a role in tumour microvascular density. To delineate tumour cell growth, angiogenesis. Growth hormone (GH) is mitogenic for a variety immunohistochemical analysis of cycling nuclear protein and of of vascular tissue cells, including smooth muscle cells, fibroblasts proliferating cell nuclear antigen, using Ki-67 and PCNA and endothelial cells and exerts its regulatory functions in polyclonal antibodies respectively, was used to demonstrate controlling metabolism, balanced growth and differentiated cell proliferative indexes. Results show that, compared to their expression by acting on specific membrane-bound receptors, normal tissue counterparts, nuclear and cytoplasmic expression which trigger a phosphorylation cascade resulting in the of GHR consistently result in strong receptor immunoreactivity modulation of numerous signalling pathways and of gene in the highly malignant angiosarcomas and Kaposi’s sarcomas expression. Essential to the initiation of a cellular response to and was localized in the cell membranes and cytoplasm, but GH, the presence of receptors for this hormone may predict the strong nuclear immunoreactivity was also identified. The adaptation of tumour cells resulting from GH exposure. To presence of intracellular GHR is the result of endoplasmic address the site/mode of action through which GH exerts its reticulum and Golgi localization. Nuclear localization is due to effects, a well characterized monoclonal antibody, obtained by identical nuclear GHR-binding protein. Furthermore, there was hybridoma technology from Balb/c mice immunized with a positive correlation of GHR immunoreactivity with neoplastic purified rabbit and rat liver GH-receptor (GHR) and directed cellular proliferation and cycling, as measured by Ki-67 and against the hormone binding site of the receptor, was applied, PCNA. In conclusion, this study shows that GHR expression in using the ABC technique to determine GHR expression in a vascular tumours is a function of malignancy and cancer panel of vascular tumours. The GHR was cloned from a rabbit progression. Malignant cells, which are highly expressive of the liver cDNA library with the aid of an oligonucleotide probe receptor, have a greater proliferation rate and thereby also higher based on a 19 residue tryptic peptide sequence derived from survival rate compared to tumours expressing lower or minimal 5900 fold purified rabbit liver receptor. A total of 64 benign and receptor level. The presence of GHR in endothelial cells of malignant vascular tumours were obtained from different vascular neoplasm indicates that they are target cells and GH is human organ sites, including the chest wall, skin, axillary of importance in the proliferation of vascular tumour angiogenesis. GH is necessary not only for differentiation of progenitor cells, but also for their subsequent clonal expansion and maintenance. The results support the hypothesis that GH is Correspondence to: David T. Lincoln, Entity Systems, Independent involved in the paracrine-autocrine mechanism, acting locally Research Foundation, 53 Ashburton Street, Chapel Hill, QLD. 4069. in regulating vascular tumour growth and will be useful for site- Australia. Tel/Fax: +61 738782417, e-mail: [email protected] specific studies of the evolution of vascular cancers. The use of Key Words: Vascular tumours, growth hormone, growth hormone anti-GHR antibodies to block tumour progression is an receptor, cellular proliferation. intriguing possibility. 0250-7005/2007 $2.00+.40 4201 ANTICANCER RESEARCH 27: 4201-4218 (2007) Vascular tumours are common lesions of the skin and factors and cytokines, stimulating non-endothelial cells. subcutaneous tissue, but also occur in many other tissues and These molecules are produced by tumour cells or tumour- internal organs. The well differentiated tumours show infiltrating lymphocytes and can also be secreted by the irregular anastomosing, blood-filled vascular channels, lined extracellular matrix. A tumour can directly stimulate by variably atypical endothelial cells. The less differentiated endothelial cells by secreting inducers, such as VEGF or tumours may show solid strands and sheets, resembling hepatocyte growth factor (HGF), that specifically bind to carcinoma or lymphoma. The tumours are a heterogenous endothelial cell receptors. On the other hand, stimulation group of neoplasms, ranging from very benign haemangiomas, can occur indirectly and less specific in that the tumour to intermediate haemangioendothelioma lesions that are secretes enzymes which release growth factors, including locally aggressive but infrequently metastasize, to highly bFGF, that are stored in the extracellular matrix. A number malignant angiosarcomas and Kaposi’s sarcomas. In general, of growth factors (GF), including insulin, VEGF, PDGF vascular neoplasms are divided into benign and malignant and EGF, acting by binding to the cell surface receptors, are tumours on the basis of two major anatomical characteristics, high-affinity ligands for transmembrane receptors belonging namely the degree to which the neoplasm is composed of well- to the family of receptor tyrosine kinases (RTKs) and play a formed vascular channels, and secondly the abundance and role in human disease, including developmental disorders of regularity of the endothelial cell proliferation. Benign vascular cancer (1). Each type of ligand binds to the extracellular tumours are made up largely of well-formed vessels with a domain of its own specific receptor. significant amount of regular endothelial cell proliferation, Growth hormone (GH) is also mitogenic for a variety of whereas, on the opposite of the spectrum, the malignant vascular tissue cells, including smooth muscle cells, fibroblasts, tumours are solidly cellular and anaplastic, with scant numbers adipocytes, macrophages, lymphocytes, endothelial cells and of only abortive vascular channels. The endothelial nature and exerts its regulatory functions in controlling metabolism, the angiogenic profile of the neoplastic proliferations that do balanced growth and differentiated cell expression by acting not form distinct vascular lumina, can be identified with the on specific membrane-bound receptors. It modulates the aid of immunocytochemical techniques using monoclonal synthesis of multiple mRNA species, including that of insulin- antibodies (MAbs) against adhesion molecules such as CD- like growth factor-1 (IGF-1), facilitating paracrine/autocrine 31, associated with platelet adhesion in inflammation and interactions in mammalian tissues. The original somatomedin wound healing. hypothesis suggested that the mitogenic growth promoting The ability of vascular cells to respond appropriately to effects of GH were mediated by circulating serum factors extracellular stimuli is essential to their growth and survival known as somatomedins or insulin-like growth factors (IGFs), in vivo, as well as to the growth, health, and survival of the produced by the liver in response to GH, the latter being organism. Growth factors and other soluble polypeptides synthesized in the pituitary gland. However, evidence from bind to their respective receptors on the cell surface, animals and developing humans has clearly demonstrated that triggering a variety of signal transduction pathways that IGF-1 is also widely synthesized locally in many tissues and often involve tyrosine phosphorylation of the receptor or the concept, that it may be directly regulated by local action of other intracellular proteins. The activation of these GH to promote both stem cell differentiation and signalling cascades then leads to the stimulation or proliferation in vitro and in vivo became established. Green et repression of specific genes in the nucleus, thus linking al. (2) have proposed a "dual effector" hypothesis of GH external stimuli to the cell’s genetic machinery. A number action, in that GH promotes differentiation of stem cell of growth factors play important roles in
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