Original contributionThe activated nerve growth factor receptor p-TrkA is selectively expressed in advanced-stage ovarian carcinoma☆
Introduction
Ovarian cancer is the most lethal gynecological malignancy in the industrialized world. Two thirds of the patients with carcinomas are diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III to IV disease, resulting in a 5-year survival of 40% [1]. Borderline tumors (tumors of low malignant potential) have low recurrence rate (7%) and an excellent 10-year survival rate (95%) [2], [3]. Although serous borderline tumors are hypothesized to be the precursors of low-grade serous carcinoma, there is lack of a widely accepted tumor progression model for high-grade carcinomas that constitute most cases [4]. We therefore need to improve our understanding of the molecular events that are unique for these tumors and those that occur in the transition from early- to late-stage disease.
Cancer is a disease of uncontrolled cell growth that is characterized by imbalance between growth and apoptosis. Tyrosine kinase growth factor receptors are overexpressed in many cancers [5]. Nerve growth factor (NGF) is the prototype molecule of the neurotrophin family. NGF binds to the tyrosine kinase high-affinity receptor TrkA and to the low-affinity receptor p75. Binding of NGF to TrkA results in intracellular signaling through the mitogen-activated protein kinase (MAPK) and phosphatdylinositol-3 kinase (PI3K)/AKT pathways. TrkA activation induces cell death of neural tumor cells and augments survival and differentiation of neurons [6]. A growing body of evidence supports the role for NGF receptors in tumorigenesis in nonneural tumors. NGF induces cell proliferation in a number of breast cancer cell lines via activation of TrkA and MAPK signaling [7]. Overexpression of TrkA receptors in animal models increased the tumorigenicity of pheochromocytoma and of prostatic and pancreatic adenocarcinoma cells [8], [9]. Rearrangement or mutation of the TrkA gene, resulting in constitutive activation of the receptor, has been observed in papillary thyroid carcinomas, as well as in acute myeloid leukemia [10], [11]. Elevated TrkA expression showed an association with tumor progression in medullary thyroid carcinoma [10]. We have demonstrated that activated TrkA (p-TrkA) is expressed in ovarian and breast adenocarcinomas, in malignant mesothelioma, and in melanoma [12], [13], [14], [15], [16]. P-TrkA expression was up-regulated in metastatic lesions in breast carcinoma and mesothelioma [14], [15] and correlated with poor overall survival in ovarian carcinoma [13].
p75, an additional neutrophin receptor, belongs to the tumor necrosis receptor family, has a different structure from TrkA, lacks intrinsic catalytic activity, and is able to bind all neurotrophins [17]. Expression of p75 has been shown in some neural and soft tissue tumors, whereas most carcinomas were negative [18]. In experimental models, p75 expression suppresses growth and metastasis of prostate cancer cells in vitro [19], [20], and expression of this receptor reduces NGF-mediated growth in this malignancy through the induction of apoptosis [20]. In prostate carcinoma, p75 expression has been found to be reduced compared to nonneoplastic tissue [21], although the latter finding was not confirmed in an additional study [22]. We have previously found generally less expression of p75 in ovarian carcinomas and mesothelioma compared with p-TrkA expression, with reduced expression in metastatic cells in effusions compared with solid lesions in breast carcinoma and mesothelioma [12], [14], [15].
The aim of the current study was to analyze the association between NGF receptor expression and the malignant potential in ovarian tumors by comparing the expression of p-TrkA and p75 in borderline tumors and invasive carcinomas. The role of these receptors in disease progression was analyzed by comparing FIGO stage I and advanced-stage (III-IV) ovarian carcinomas. Finally, we evaluated the relationship between MAPK activation and NGF receptor expression status in borderline tumors and FIGO stage I carcinomas.
Section snippets
Patients and material
The studied material consisted of 119 primary borderline ovarian tumors (65 serous, 53 mucinous, 1 endometrioid), 57 primary stage I carcinomas (16 serous, 10 mucinous, 11 endometrioid, 15 clear cell tumors, 4 mixed epithelial tumors, and 1 undifferentiated carcinoma), and 56 advanced-stage ovarian carcinomas. The last group consisted of 24 primary and 32 metastatic lesions (18 omental, 5 peritoneal, and 9 from other sites) from 27 patients, all of the serous type except for 1 tumor that showed
p-TrkA expression is up-regulated in advanced-stage ovarian carcinomas
p-TrkA IHC results are shown in Table 1. Membrane expression was detected in 21 (18%) of 119 borderline tumors, 12 (21%) of 57 stage I carcinomas, and 47 (84%) of 56 stage III to IV carcinomas (Fig. 1A-C). Statistical analysis showed significant up-regulation of p-TrkA in advanced-stage carcinomas (P < .001, χ2 test). There was no significant difference between borderline tumors and stage I ovarian carcinomas or between tumors of different histological types in these diagnostic categories.
Discussion
Despite an initial response to surgery combined with chemotherapy, patients with advanced-stage ovarian carcinoma are rarely cured, and long-term survival is the exception rather than the rule in this disease. In contrast, borderline tumors and stage I carcinomas are associated with good prognosis in most of the cases. Although the degree of malignancy (ie, borderline versus invasive carcinoma and histological grade) and tumor stage are the main factors determining disease outcome,
Acknowledgments
We are grateful for the competent technical assistance from Ms Inger-Liv Nordli, Ms Mai Nguyen, and Ms Ann Larsen (immunohistochemistry) at the Department of Pathology, National Hospital-Norwegian Radium Hospital.
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2016, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :In a study including specimens from 119 borderline tumors, 57 FIGO stage I invasive ovarian carcinomas, and 56 advanced-stage carcinomas, phospho-TrkA membrane expression was significantly more present in advanced cancer, whereas p75NTR expression was not different between different stages [76]. In accordance with its pro-apoptotic role, phospho-JNK expression was more prevalent in stage I ovarian cancer [76]. Interestingly, the increased phospho-TrkA expression did not correlate to MAPK activation in this cohort, suggesting a MAPK-independent signaling in ovarian cancer [76].
Role of the JNK Pathway in human diseases
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Tyrosine kinase A receptor (trkA): A potential marker in epithelial ovarian cancer
2011, Gynecologic OncologyCitation Excerpt :Nevertheless, NGF and trkA involvement in EOC initiation and progression have not been adequately established. Increased p-trkA expression has been described in advanced ovarian carcinomas [12], and the co-expression of NGF with angiogenesis-related molecules and p-trkA expression in endothelial cells suggest that both the in vitro and in vivo pro-angiogenic roles of NGF could be relevant in ovarian cancer. Therefore, the objective of the present study was to examine if trkA receptor may be used as a potential tumor marker in EOC.
Peaceful use of disastrous neurotoxicants
2010, NeuroToxicologyEffect of acetyl-l-carnitine on ovarian cancer cells' proliferation, nerve growth factor receptor (Trk-A and p75) expression, and the cytotoxic potential of paclitaxel and carboplatin
2009, Gynecologic OncologyCitation Excerpt :Advanced stage ovarian tumors also express the NGFR p75 and Trk-A [31,32]. In one study, expression of phosphorylated Trk-A NGFR was observed in 21 (18%) of 119 borderline, 12 (21%) of 57 stage I, and 47 (84%) of 56 stage III-IV ovarian carcinomas [32]. The significance of these observations is that stimulation of NGFR expressing ovarian cancer cell lines with NGF induces the cells to produce VEGF [33].
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The work of EØ is supported by research grants from Ulleval University Hospital, Oslo, Norway, and Eastern Norway Regional Health Authority, Hamar, Norway.