HGF／c—Met系统在鼻咽癌中的表达及其与增殖细胞核抗原的关系

目的：探讨HGF／c—Met在鼻咽癌（NPC）中的表达及与PCNA的关系。方法：采用免疫组织化学s—P法检测55例NPC,15例慢性鼻咽炎症中HGF／c—Met蛋白的表达;并检测55例NPC组织中的癌细胞PCNA增殖指数。结果：HGF、c—Met在慢性鼻咽黏膜炎症中,主要表达于柱状上皮细胞胞膜或细胞浆;在NPC中HGF主要表达于肿瘤间质、癌细胞有少量表达;c—Met表达于癌细胞,间质不表达。HGF、C—Met蛋白在NPC中的阳性表达率分别为90．9％（50／55）、70．9％（39／55）,与对照组相比,差异有显著性（P〈0．05或P〈0．01）;HGF,c—Met阳性表达与临床分期呈正相关（P〈0．05）,而与年龄、性别、组织分型无相关性（P〉0．05）;有淋巴结转移的c—Met蛋白阳性表达率显著高于无淋巴结转移,差异有显著性（P〈0．05）。HGF、c—Met蛋白的表达与NPC的PCNA增殖指数呈显著正相关（rs=0．8611、P〈0．01和rs=0．8480、P〈0．01）。结论：c—Met基因的异常表达与NPC侵袭转移生物学行为密切相关,c—Met对于判断NPC预后具有一定价值。HGF／c—Met可能在癌细胞增殖和侵袭转移过程中起调节作用,HGF／c—Met过度表达者,NPC血管生成能力显著增强、癌细胞增殖活跃,更易发生转移。     

Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture.

Activation of Met by its ligand HGF has been shown to elicit both mitogenic and motogenic responses in thyrocytes in vitro. In the present study we have investigated the expression of Met in human anaplastic thyroid carcinoma cells in culture. There was a variation in expression level and size of Met in the different cell lines; high Met expression was found in four cell lines, compared to non-neoplastic human thyrocytes. Treatment with glucoproteinase F showed that the size differences observed were due to variances in the degree of glycosylation. Interestingly, in cell lines with high expression of Met, the receptor proteins were found to be constitutively tyrosine phosphorylated. None of these cell lines expressed HGF mRNA, and addition of suramin did not affect the level of tyrosine phosphorylation of Met in unstimulated cells, suggesting the absence of autocrine stimulatory pathways. Furthermore, we did not observe MET gene amplification, activating mutations or phosphatase defects. The tyrosine phosphorylated receptors appeared functionally active since the receptors associated with the adaptor molecule Shc. In summary, we have found ligand-independent constitutively activated Met in four out of six anaplastic thyroid carcinoma cell lines.     

The tyrosine kinase receptor met and its ligand HGF are co-expressed and functionally active in HHV-8 positive primary effusion lymphoma.

Primary effusion lymphoma (PEL) harbors consistent infection by human herpesvirus-8, preferentially develops in immunodeficient patients and selectively localizes to the serous body cavities. Histogenetic analysis has suggested that PEL originates from post-germinal center, pre-terminally differentiated B cells sharing phenotypic features with plasma cells. Here we have investigated the expression status and functional integrity of the Met tyrosine kinase receptor and of its ligand hepatocyte growth factor (HGF). Thirteen PEL (nine cell lines and four primary specimens) were analyzed for Met and HGF expression and function by multiple assays. For comparison, a panel of 34 high grade B cell non-Hodgkin lymphomas (NHL) other than PEL was also investigated. Co-expression of Met and HGF was found in all PEL analyzed, whereas it was restricted to 1/34 B cell NHL other than PEL (P < 0.001; chi2 test). The Met protein expressed by PEL displays biochemical characteristics typical of Met expressed by other cell types and is capable of tyrosine autophosphorylation. By using a combination of immunological and biological assays, production and secretion of a functional HGF species was identified in all PEL cell lines analyzed. HGF stimulation of PEL cells rapidly induces Met tyrosine phosphorylation, demonstrating the functional integrity of the Met/HGF loop. Because of the well known mitogenic and motogenic properties of Met/HGF interactions, these data may bear implications for PEL growth and dissemination. Among B cell neoplasms, Met/HGF co-expression selectively clusters with PEL and, as demonstrated by previous studies, with multiple myeloma plasma cells, thus reinforcing the notion that PEL displays biologic similarities with tumors derived from late stages of B cell differentiation.     

Expression of the Met/HGF receptor in normal and neoplastic human tissues.

The MET oncogene encodes a transmembrane tyrosine kinase receptor. Recently, hepatocyte growth factor (HGF), a potent growth factor for hepatocytes involved in liver regeneration, has been proposed as a ligand. In this paper, the physiological role of the human Met/HGF receptor is investigated by studying its specific distribution in normal and neoplastic tissues. Northern blot analysis has shown that the MET gene is selectively expressed in several epithelial tissues. High levels of MET mRNA have been found in liver, gastrointestinal tract, thyroid and kidney. Western blot analysis has shown that the levels of the Met protein generally correspond to those of the mRNA. However, in the thyroid, where there is a high level of MET mRNA, the protein was barely detectable, suggesting translational or post-translational regulation. The protein was also detected in the brain. Normal or increased levels of MET mRNA and Met protein were consistently found in fresh samples of carcinomas as well as in epithelial tumor cell lines. In thyroid carcinomas of a specific histiotype the amount of Met protein, almost undetectable in the normal counterpart, was found to be increased more than 100-fold. The tissue distribution of the Met/HGF receptor indicates that this molecule is involved in growth control of epithelial cells other than hepatocytes and suggests that its increased expression may confer a growth advantage to neoplastic cells.     

Increased production and secretion of HGF α‐chain and an antagonistic HGF fragment in a human breast cancer progression model

Invasive human breast carcinomas frequently coexpress increased hepatocyte growth factor (HGF) and its receptor Met, suggesting that establishment of an autocrine HGF loop is important in malignant disease. This study examines the expression patterns of HGF and Met activation during tumorigenesis and metastasis using a MCF10A‐based model of Ha‐Ras‐induced human breast cancer progression. Deregulation of cadherin‐based cell‐cell adhesions, decreased expression of cytokeratins 8/18 and increased activity of matrix metalloproteinases such as MMP‐2 occurs in premalignant and malignant (metastatic) cell lines compared to the parental nonmalignant cell line. Compared to the benign parent cell line, premalignant and malignant cell lines exhibit increased secretion of full length HGF α‐chain and elevated Met tyrosine phosphorylation in complete medium. Interestingly, the premalignant and malignant cells also secrete a ～55 kDa HGF fragment. Epitope mapping of the ～55 kDa HGF fragment supports the presence of the N‐terminal domain of the HGF α‐chain with a truncation in the C‐terminal domain. The ～55 kDa HGF fragment shows mobility in SDS‐PAGE faster than HGF α‐chain, but slightly slower than NK4, a previously established full antagonist of HGF. The separated ～55 kDa HGF fragment binds to animmobilized Met‐IgG fusion protein, and inhibits both HGF/Met‐IgG binding and HGF‐induced Met‐tyrosine phosphorylation. These results are the first demonstration of an antagonistic ～55 kDa HGF fragment secreted during breast carcinoma progression, which may have a negative regulatory effect on HGF signaling in premalignant breast epithelial cells. © 2009 UICC     

趋化因子受体CXCR4在鼻咽癌中的表达及意义

目的探讨趋化因子受体CXCR4在人鼻咽癌中的表达及临床意义。方法采用Real-timeRT-PCR法检测鼻咽癌细胞株中CXCR4mRNA的表达,应用免疫组织化学法并结合组织阵列检测正常鼻咽组织、鼻咽癌和鼻咽癌淋巴结转移石蜡组织标本中CXCR4蛋白的表达情况。结果在7种鼻咽癌细胞株中,CXCR4基因在高成瘤、高转移潜能的5-8F细胞中表达水平最高,在无转移能力的610B细胞中表达最低。CXCR4蛋白在正常鼻咽组织、鼻咽癌和鼻咽癌淋巴结转移组织中表达差异具有统计学意义（P=0．002）;鼻咽癌组织中CXCR4表达高于正常鼻咽组（P=0．029）;伴发转移的鼻咽癌组织比未发生转移的鼻咽癌组织CXCR4表达增强,差异具有统计学意义（P=0．008）;淋巴结转移癌组织CX-CR4表达比鼻咽癌组织高（P=0．013）。结论本研究提示CXCR4表达与鼻咽癌转移存在密切关系,CXCR4表达可作为鼻咽癌转移过程中一个有价值的指标。     

Over‐expression of phosphatase of regenerating liver‐3 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma

This study aimed at clarifying the expression of phosphatase of regenerating liver‐3 (PRL‐3), one member of protein tyrosine phosphatase (PTP) superfamily, in nasopharyngeal carcinoma (NPC) and its correlation with clinicopathologic features, including the survival of patients with NPC. Real‐time PCR and Western blot showed that the expression level of PRL‐3 was markedly higher in NPC cell lines than that in the normal nasopharyngeal epithelial cell at both mRNA and protein levels. Immunohistochemical analysis revealed overexpression of PRL‐3 in 97 of 174 (55.7%) paraffin‐embedded archival NPC biopsies. Statistical analysis showed that PRL‐3 expression was positively correlated with N classification (p = 0.033), distant metastasis (M classification, p = 0.048) and clinical stage (p = 0.005) of patients. Patients with higher PRL‐3 expression had shorter overall survival time, whereas patients with lower level of PRL‐3 had better survival. Multivariate analysis suggested that PRL‐3 expression might be an independent prognostic indicator for the survival of patients with NPC. Disruption of endogenous PRL‐3 protein through a siRNA knockdown technique was shown to suppress the invasion ability and migration potency of 5‐8F and HONE1 cells, substantially. Interestingly, we also found that no significant effect on the proliferation of 5‐8F and HONE1 cells was observed after PRL‐3 was down‐regulated. Our results suggest that PRL‐3 protein is a valuable marker for progression of NPC patients. High PRL‐3 expression is associated with poor overall survival in patients with NPC. © 2008 Wiley‐Liss, Inc.     

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma.

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.     

Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met

ABSTRACT: INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown clinical efficacy in lung, colon, and pancreatic cancers. In lung cancer, resistance to EGFR TKIs correlates with amplification of the hepatocyte growth factor (HGF) receptor tyrosine kinase Met. Breast cancers do not respond to EGFR TKIs, even though EGFR is overexpressed. This intrinsic resistance to EGFR TKIs in breast cancer does not correlate with Met amplification. In several tissue monoculture models of human breast cancer, Met, although expressed, is not phosphorylated, suggesting a requirement for a paracrine-produced ligand. In fact, HGF, the ligand for Met, is not expressed in epithelial cells but is secreted by fibroblasts in the tumor stroma. We have identified a number of breast cancer cell lines that are sensitive to EGFR TKIs. This sensitivity is in conflict with the observed clinical resistance to EGFR TKIs in breast cancers. Here we demonstrate that fibroblast secretion of HGF activates Met and leads to EGFR/Met crosstalk and resistance to EGFR TKIs in triple-negative breast cancer (TNBC). METHODS: The SUM102 and SUM149 TNBC cell lines were used in this study. Recombinant HGF as well as conditioned media from fibroblasts expressing HGF were used as sources for Met activation. Furthermore, we co-cultured HGF-secreting fibroblasts with Met-expressing cancer cells to mimic the paracrine HGF/Met pathway, which is active in the tumor microenvironment. Cell growth, survival, and transformation were measured by cell counting, clonogenic and MTS assays, and soft agar colony formation, respectively. Student's t test was used for all statistical analysis. RESULTS: Here we demonstrate that treatment of breast cancer cells sensitive to EGFR TKIs with recombinant HGF confers a resistance to EGFR TKIs. Interestingly, knocking down EGFR abrogated HGF-mediated cell survival, suggesting a crosstalk between EGFR and Met. HGF is secreted as a single-chain pro-form, which has to be proteolytically cleaved in order to activate Met. To determine whether the proteases required to activate pro-HGF were present in the breast cancer cells, we utilized a fibroblast cell line expressing pro-HGF (RMF-HGF). Addition of pro-HGF-secreting conditioned fibroblast media to TNBC cells as well as co-culturing of TNBC cells with RMF-HGF fibroblasts resulted in robust phosphorylation of Met and stimulated proliferation in the presence of an EGFR TKI. CONCLUSIONS: Taken together, these data suggest a role for Met in clinical resistance to EGFR TKIs in breast cancer through EGFR/Met crosstalk mediated by tumor-stromal interactions.     

鼻咽癌细胞中Survivin基因的转录和表达

目的研究新的凋亡抑制因子Survivin基因在人鼻咽癌高分化上皮细胞株CNE-1和低分化上皮细胞株CNE-2Z中的转录和表达.方法分别提取2种细胞总RNA,用逆转录PCR检测Survivin基因的转录;同时制备2种细胞的蛋白质样品,经免疫印迹检测Survivin基因的表达.结果Survivin基因在人鼻咽癌高、低分化细胞株中均有表达,其表达量差异无显著意义.结论Survivin的表达可能与鼻咽癌细胞分化程度无明显关系,但Survivin基因可能与鼻咽癌的发生、发展和预后不良有关.     

PTEN与Bcl-2在鼻咽癌中的表达及意义

目的 观察PTEN与Bcl-2在鼻咽癌(NPC)中的表达情况,探讨两者的表达及其联合表达在NPC发生、发展、侵袭和转移过程中的可能作用。方法 采用免疫组织化学染色法,观察50例NPC 石蜡标本和15例正常鼻咽黏膜标本中PTEN与Bcl-2的蛋白表达情况。结果 正常鼻咽组织中,PTEN呈强阳性表达,而Bcl-2的表达仅局限在上皮层的基底细胞层。NPC中,PTEN阳性表达率为22.0%(11/50),Bcl-2为82.0%(41/50),与正常组比较,差异均有统计学意义。两者在NPC的表达强度无明显相关(r=－0.109,P=0.453)。结论 在NPC组织中,PTEN的低表达或表达缺失和Bcl-2强阳性表达可能协同参与了NPC的发生,而在NPC的发展、浸润和转移过程中,两者未能表现出明显的相关性。     

Overexpression of the MET/HGF receptor in ovarian cancer

The MET oncogene encodes the receptor for Hepatocyte Growth Factor/Scatter Factor, a unique growth factor that induces not only proliferation of epithelial cells, but also cell motility and invasiveness. DNA level and expression of the Met/HGF receptor gene were examined with Southern- and Western-blot analyses, respectively, in human ovary, benign ovarian tumors and epithelial ovarian carcinomas. The Met/HGF receptor was detectable in the surface epithelium of normal ovary. The level of expression was unchanged in benign ovarian tumors of various origins. Fourteen out of 67 malignant carcinomas (20%) showed a 3-to 10-fold increase in expression. In 5 additional cases the Met/HGF protein was overexpressed over 50-fold. This represents a total of 28% of cases. Overexpression was not associated with MET gene amplification. Overexpressing tumors belonged to different histotypic variants, but showed a well-differentiated phenotype. Clinically, overexpression was associated with disease at any pathologic stage, but was significantly correlated with premenopausal status of patients. These data suggest that expression of the Met/HGF receptor may add a selective growth advantage to a narrow subset of differentiated ovarian cancers in premenopausal patients.     

蛋白酶活化受体-1在鼻咽癌中的表达及意义

目的检测PAR1在鼻咽癌中的表达,探讨PAR1在鼻咽癌中表达的意义。方法免疫组织化学（SP法）检测28例良性鼻咽组织、61例鼻咽癌组织中PAR1中的表达;采用RT-PCR、Western Blot检测鼻咽癌细胞系CNE-1、CNE-2中PAR1表达并比较其表达差异。结果PAR1在鼻咽癌组织及两种鼻咽癌细胞株中均表达。PAR1在28例良性鼻咽组织表达为10例,61例鼻咽癌组织中表达48例。PAR1在鼻咽癌组织中的表达率明显高于在良性鼻咽组织中的表达率（P〈0．01）,高度恶性细胞株中PAR1的表达明显高于其低度恶性细胞株。结论PAR1的表达与鼻咽癌的发生、生长方式、分期、恶性程度等有关。PAR1在鼻咽癌中的表达可能介导鼻咽癌侵袭转移等恶性生物学行为。     

CSPG4基因在鼻咽癌中的表达分析

  目的  研究硫酸软骨素多糖蛋白4（CSPG4）基因在鼻咽癌及对照组织中的表达。  方法  采用实时荧光定量PCR测定CSPG4基因在4例正常鼻咽上皮和18例鼻咽癌组织（其中Ⅱ期6例,Ⅲ期5例,Ⅳ期7例）中的表达情况;通过构建包含92例对照和187例鼻咽癌的组织芯片,应用免疫组织化学检测CSPG4蛋白的表达和分布。  结果  正常鼻咽上皮中CSPG4基因mRNA表达水平较低,在鼻咽癌中CSPG4表达上调且与临床分期呈正相关,差异具有统计学意义（P=0.017）。免疫组织化学结果表明鼻咽癌中CSPG4蛋白表达水平高于对照组,91.98%的鼻咽癌组织中CSPG4为强阳性表达,而对照组的强阳性率为76.09%（P=0.001）。  结论  CSPG4在鼻咽癌中随着临床进展表达逐渐上调,可能参与了鼻咽癌的发生发展,具体机制及临床应用前景值得进一步深入研究。      

Expression of Etk/Bmx tyrosine kinase in the tumorigenicity of nasopharyngeal epithelium and its relation with EB virus infection and the apoptosis-related protein Bcl-2

We compared Etk/Bmx expression in nasopharyngeal carcinoma (NPC) and non-neoplastic nasopharyngeal lesions in order to learn whether the expression of this non-receptor protein tyrosine kinase is associated with the development of NPC. We also related Etk/Bmx expression to factors resulting from Epstein-Barr virus (EBV) infection. We used immunohistochemistry (IHC) and in situ hybridization to examine 20 non-neoplastic nasopharyngeal lesions and 49 cases of NPC to assess Etk/Bmx, EB virus latent membrane protein-1 (LMP-1), Bcl-2 and EBV-encoded small RNA-1 expression in these samples. Etk/Bmx expression was present in the basal cell nuclei of the nasopharyngeal epithelium in 1/9 (11.1%) cases of chronic nasopharyngitis and 2/11 cases (18.2%) of dysplasia. While 13/49 (26.5%) NPC cases expressed Etk/Bmx, the difference in frequency between the expression of Etk/Bmx in the non-neoplastic and NPC cases was not significant. Etk/Bmx expression was correlated with the presence of EBER-1 immunopositivity in dysplasia and in NPC but not in chronic nasopharyngitis. The presence of Etk/Bmx immunopositivity was independent of the expression of either LMP-1 or Bcl-2 in either the nasopharyngeal carcinoma or the non-neoplastic lesions. This suggests that in some cases of non-neoplastic and neoplastic nasopharyngeal lesions, Etk/Bmx may participate in regulating epithelial differentiation. While EBV-related small RNA-1 may participate in this regulation, neither LMP-1 or Bcl-2 expression appears to be related to Etk/Bmx expression.     

鼻咽癌不同转移潜能细胞株基因表达的差异

目的：描绘鼻咽癌细胞株不同转移潜能亚株的基因表达谱,以筛选鼻咽癌新的肿瘤相关及转移相关候选基因,方法：用含14000个cDNA克隆的表达微阵列分析鼻咽癌细胞株SUNE－1的3个亚株,即高转移潜能细胞株5－8F,成瘤不转移株6－10B和不成瘤株13－9B的mRNA表达;用半定量RT－PCR验证cDNA表面微阵列检测的结果。结果：5－8F与13－9B比较,有82个差异表达基因;6－10B与13－9B比较,有38个差异表达基因,5－8F与6－10B比较,有54个差异表达基因,5－8F及6－10B与13－9B比较,有12个共有的差异表达基因;5－8F与13－9B及6－10B比较,有14个共有的差异表达基因。这些基因涉及代谢,转录,分化,凋亡和信号转导等多种生物功能以及许多未知功能,结论：揭示了鼻咽癌细胞株的基因表达谱,为寻找鼻咽癌相关基因提供了重要线索。     

Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor involved both in development and tissue repair, as well as pathological processes such as cancer and metastasis. It has been identified in vivo in many types of tumours together with its tyrosine kinase receptor, Met. We show here that exogenous HGF/SF acts as a strong chemoattractant for human mesothelioma cell lines. The factor also enhanced cell adhesion to and invasion into Matrigel. The mesothelioma cell lines synthesized a panel of matrix metalloproteinases critical for tumour progression such as MMP-1, 2, 3, 9 and membrane-bound MT1-MMP. HGF/SF stimulated the expression of MMP-1, 9 and MT1-MMP and had a slight effect on expression of the MMP inhibitor TIMP-1 but not TIMP-2. However, there was no simple correlation between the levels of MMPs and TIMPs of the cell lines and their different invasion properties or between HGF/SF stimulatory effects on MMP expression and invasion. In addition, effects of protease inhibitors on invasion suggested that serine proteases were also expressed in human mesothelioma cell lines and were involved in HGF/SF-induced invasion. The results show a predominant role for HGF/SF in mesothelioma cell invasion, stimulating simultaneously adhesion, motility, invasion and regulation of MMP and TIMP levels.     

Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis?

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n=20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.