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Autocrine production of reproductive axis neuropeptides affects proliferation of canine osteosarcoma in vitro

Osteosarcoma strikes hundreds of people each year, of both advanced and younger ages, and is often terminal. Like many tumor types, these bone tumors will frequently undergo a neuroendocrine transition, utilizing autocrine and/or paracrine hormones as growth factors and/or promoters of angiogenesis...

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Published in:BMC cancer 2019-02, Vol.19 (1), p.158-158, Article 158
Main Authors: Weinman, Marcus A, Fischer, Jacob A, Jacobs, Dakota C, Goodall, Cheri P, Bracha, Shay, Chappell, Patrick E
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description Osteosarcoma strikes hundreds of people each year, of both advanced and younger ages, and is often terminal. Like many tumor types, these bone tumors will frequently undergo a neuroendocrine transition, utilizing autocrine and/or paracrine hormones as growth factors and/or promoters of angiogenesis to facilitate progression and metastasis. While many of these factors and their actions on tumor growth are characterized, some tumor-derived neuropeptides remain unexplored. Using validated canine osteosarcoma cell lines in vitro, as well as cells derived from spontaneous tumors in dogs, we explored the autocrine production of two neuropeptides typically found in the hypothalamus, and most closely associated with reproduction: gonadotropin-releasing hormone (GnRH) and kisspeptin (Kiss-1). We evaluated gene expression and protein secretion of these hormones using quantitative RT-PCR and a sensitive radioimmunoassay, and explored changes in cell proliferation determined by MTS cell viability assays. Our current studies reveal that several canine osteosarcoma cell lines (COS, POS, HMPOS, D17, C4) synthesize and secrete GnRH and express the GnRH receptor, while COS and POS also express kiss1 and its cognate receptor. We have further found that GnRH and kisspeptin, exogenously applied to these tumor cells, exert significant effects on both gene expression and proliferation. Of particular interest, kisspeptin exposure stimulated GnRH secretion from COS, similarly to the functional relationship observed within the neuroendocrine reproductive axis. Additionally, GnRH and kisspeptin treatment both increased COS proliferation, which additionally manifested in increased expression of the bone remodeling ligand rankl within these cells. These effects were blocked by treatment with a specific GnRH receptor inhibitor. Both neuropeptides were found to increase expression of the specific serotonin (5HT) receptor htr2a, the activation of which has previously been associated with cellular proliferation, suggesting that production of these factors by osteosarcoma cells may act to sensitize tumors to circulating 5HT of local and/or enteric origin. Here we report that kisspeptin and GnRH act as autocrine growth factors in canine osteosarcoma cells in vitro, modulating RANKL and serotonin receptor expression in a manner consistent with pro-proliferative effects. Pharmacological targeting of these hormones may represent new avenues of osteosarcoma treatment.
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Both neuropeptides were found to increase expression of the specific serotonin (5HT) receptor htr2a, the activation of which has previously been associated with cellular proliferation, suggesting that production of these factors by osteosarcoma cells may act to sensitize tumors to circulating 5HT of local and/or enteric origin. Here we report that kisspeptin and GnRH act as autocrine growth factors in canine osteosarcoma cells in vitro, modulating RANKL and serotonin receptor expression in a manner consistent with pro-proliferative effects. 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subjects Angiogenesis
Autocrine
Autocrine signalling
Bone cancer
Bone remodeling
Bone tumors
Breast cancer
Cell adhesion & migration
Cell growth
Cell proliferation
Colorectal cancer
Gene expression
GnRH
Gonadotropin-releasing hormone
Gonadotropins
Growth factors
Hormones
Hypothalamus
Kinases
Kiss1 protein
Kisspeptin
Ligands
Medical prognosis
Metastases
Metastasis
Neuropeptides
Osteosarcoma
Osteosarcoma cells
Paracrine signalling
Pituitary (anterior)
Polymerase chain reaction
Proliferation
Proteins
Radioimmunoassay
Sarcoma
Secretion
Serotonin
TRANCE protein
Tumor cells
Tumors
title Autocrine production of reproductive axis neuropeptides affects proliferation of canine osteosarcoma in vitro
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