Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype

Abstract

Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST.

Synaptic Vesicle Protein 2 (SV2) Isoforms

“…These observations indicate that aberrant multi-lineage transdifferentiation or lineage infidelity may be a wide spread phenomenon in cancer. This is consistent with others findings of a neuroendocrine phenotype in gastrointestinal stromal tumors which regularly express synaptic vesicle proteins too (Bumming et al, 2007). All these suggest that mammary glands may have neuroendocrine functions, however, SV2 presence had not already been reported in tumor and non-tumor breast cells, and this is in part the importance of our work.…”

“…The role of SV2 in breast cells could be associated to secretory nature of mammary glands, and may interact with other vesicle proteins such as synaptobrevin, which is essential for secretion but not for the development of synaptic process (Ahnert-Hilger et al, 1996), however, the SV2 role in cancer is not clear, although it is already reported in others types of cancer, for instance, brain (de Groot et al, 2010;, pancreas (Jakobsen et al, 2002), gastrointestinal tract (Jakobsen et al, 2002;Bumming et al, 2007 ), liver (Hanoun et al, 2010), bladder (Coelho et al, 2010), prostate (Karsenty et al, 2009) and adrenals (Li et al, 1999) tumors among others, where SV2 has already been proposed as molecular and transdifferentiation marker of neural nature (Nilsson et al, 2004;Zhang et al, 2010). This is possible because in the cancerous state the terminal differentiation to the anticipated cellular type is altered and the phenomena of lineage infidelity that is associated with the ability of cancer cells to transdifferentiate, occurs in different cancer types and occur in breast cancer (Zhang et al, 2010); thus, it is a commune phenomenon that cancer cell turns-off/-on non-habitual genes changing the ontogeny to evade the immune system and hold the linage independence.…”

“…The presence of secretory vesicles is characteristic in synaptic (de Groot et al, 2010;, gastric (Bumming et al, 2007), pancreatic (Jakobsen et al, 2002), adrenal (Li et al, 1999) and prostatic (Karsenty et al, 2009) cells which synaptic vesicular receptor (SV) play an important role in exocytosis and secretory process of synaptic (de Groot et al, 2010) and endocrine cells, (Dong et al, 2006;Coelho et al, 2010), but when cancer occurs this protein tends to overexpress in brain (de Groot et al, 2010), neuroendocrine (Portela-Gomes et al, 2000), gastrointestinal (Bumming et al, 2007) and prostate (Karsenty et al, 2009) is not clear neither it has been reported in breast cells, but its role as molecular marker of cancer in others organs and tissues has been increasing in recent years (Portela-Gomes et al, 2000;Zhang et al, 2010).…”

SLITRK3 expression correlation to gastrointestinal stromal tumor risk rating and prognosis

“…Synaptic-like microvesicle proteins, such as amphiphysin, synaptic vesicle protein, SV2, and synapsin 1, are found in a majority of GISTs [9] . Expression of these proteins enables GISTs to secrete neurotransmitters or hormones, suggesting that GISTs adopt a neuroendocrine phenotype.…”

“…GABA is a key inhibitory neurotransmitter and mediates synaptic transmission, neural network development [12] , and is involved in digestive diseases such as esophageal reflux and gastric cancer [13][14][15] . GISTs may originate from the interstitial cells of Cajal (ICCs), with pacemaker potentials suggesting that mutations in genes involved in synapse or neural development may underlie GIST behavior [9] . In agreement with this, we have previously found that the expression of SLITRK3 was increased in a high-risk group compared to a low-risk group (unpublished data), and Milde et al [16] showed higher SLITRK3 expression levels in lymphoma.…”