Pathogenesis Of Clear Cell Carcinoma Research Articles

Clear Cell Renal Cell Carcinoma: From Biology to Treatment.

The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.

BRG1, INI1, and ARID1B Deficiency in Endometrial Carcinoma: A Clinicopathologic and Immunohistochemical Analysis of a Large Series From a Single Institution.

Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.

Functional Gene Clusters in Global Pathogenesis of Clear Cell Carcinoma of the Ovary Discovered by Integrated Analysis of Transcriptomes.

Clear cell carcinoma of the ovary (ovarian clear cell carcinoma (OCCC)) is one epithelial ovarian carcinoma that is known to have a poor prognosis and a tendency for being refractory to treatment due to unclear pathogenesis. Published investigations of OCCC have mainly focused only on individual genes and lack of systematic integrated research to analyze the pathogenesis of OCCC in a genome-wide perspective. Thus, we conducted an integrated analysis using transcriptome datasets from a public domain database to determine genes that may be implicated in the pathogenesis involved in OCCC carcinogenesis. We used the data obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) DataSets. We found six interactive functional gene clusters in the pathogenesis network of OCCC, including ribosomal protein, eukaryotic translation initiation factors, lactate, prostaglandin, proteasome, and insulin-like growth factor. This finding from our integrated analysis affords us a global understanding of the interactive network of OCCC pathogenesis.

CDNA expression library screening revealed novel functional genes involved in clear cell carcinogenesis of the ovary in vitro

In order to identify genes involved in the pathogenesis of clear cell carcinoma of the ovary (CCC), functional screening using a cDNA expression library was performed. We extracted mRNA from a CCC cell line (RMG-1), established a cDNA library using a retroviral vector, transfected that library into mouse NIH3T3 cells and sequenced the resultant foci. The tissue-type specific expression of isolated genes and their transforming activities were evaluated. Seven genes were isolated. Of these genes, the mRNA expression of SEC61B and DVL1 is significantly stronger in CCC than in other histological types (p < .05). Immunohistochemical staining reveals the stronger expression of SEC61B and C1ORF38 than normal ovarian tissues (p < .05). Focus formation is confirmed by the transfection of SEC61B, C1ORF38, and DVL1 into NIH3T3 cells. The present study identified novel genes including SEC61B, C1ORF38, and DVL1, involved in the pathogenesis of CCC. These genes may be additional therapeutic targets for CCC. Impact statement What is already known on this subject? Several important genetic abnormalities, including ARID1A and PIK3CA mutations, have been reported in ovarian clear cell carcinoma (CCC). What the results of this study add? SEC61B, C1ORF38, and DVL1 were newly detected as candidate genes involved in ovarian clear cell carcinogenesis. What the implications are of these findings for clinical practice and/or further research? Functional screening using a cDNA expression library may be a useful technique to identify functional genes for pathogenesis. The information obtained using this technique may provide new therapeutic targets of CCC.

Gene set-based integrative analysis of ovarian clear cell carcinoma

ObjectiveThe pathogenesis of ovarian clear cell carcinoma is still poorly understood; therefore, we conducted a gene set-based analysis by integrating datasets downloaded from publicly available microarray gene expression databases to investigate the pathogenesis of clear cell carcinoma, which was based on the regularity of functions defined by gene ontology or canonical pathway databases. Materials and MethodsThe gene expression profiles of 80 clear cell carcinomas and 136 normal ovarian controls were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity (GSR) indexes computed using the modified differential rank conservation, an algorithm measuring the degree of gene expression ranking change in a gene set. Then the differences of GSR indexes between clear cell carcinomas and normal ovarian controls were analyzed. ResultsMachine learning can accurately recognize and classify the patterns of functional regularities containing the GSR indexes between the clear cell carcinomas and normal controls with an accuracy of 99.3%. The significant aberrations included oxidoreductase activity, binding, transport, channel activity, cell adhesion, immune response, chromosome assembly, and the deregulated signaling molecules, such as guanyl nucleotide exchange factors, phosphoinositide 3-kinase-activating kinase, receptor tyrosine kinase B, and protein tyrosine kinase. ConclusionOur pioneering works using the functionome, which was converted from microarray gene expression profiles for integrative analysis, showed a clear distinction of functional changes between the clear cell carcinomas and normal ovarian controls. This approach might provide a comprehensive view of the deregulated functions of clear cell carcinomas for further investigation.

Establishment and characterization of a cell line (HCH-1) originating from a human clear cell carcinoma of the ovary.

BackgroundCell lines are very useful for both clinical and basic research. The establishment of ovarian, malignant tumor cell lines with aggressive histology is especially important. We describe the establishment and characterization of a new human clear cell carcinoma cell line of the ovary.ResultsThe cell line HCH-1 was established from an ovarian tumor from a 67-year-old woman. This cell line has grown well for 230 months and has been subcultured more than 50 times. Monolayer cultured cells are polygonal in shape, showing a pavement-like arrangement and a tendency to pile up without contact inhibition. It exhibits a human karyotype with a modal chromosomal number in the hypodiploid range. The cells could be transplanted into the subcutis of SCID mice and produced tumors resembling the original tumor. HCH-1 cells produced CA125 and CA19-9, also identified immunohistochemically in both the original tumor and the heterotransplanted tumors. The cells were sensitive to actinomycin D, carboplatin, cisplatin and mitomycin C, drugs commonly used in the treatment of gynecological cancers. Variant was not found in hotspot of the 50 most commonly reported oncogenes and tumor suppressor genes. Only 12 ovarian clear cell carcinoma cell lines and their characteristics have thus far been reported in the literature. HCH-1 is the first ovarian clear cell carcinoma cell line reported in which the chromosome number is in the hypodiploid range and only the second cell line in which CA125 and CA19-9 are expressed.ConclusionsSince it is impossible to establish a cell line from the malignant tumor of each patient, the cell line that we established, characterized and report in this paper may be very useful in basic research on ovarian cancer. We have much to learn about the pathogenesis of clear cell carcinoma and this extra line of enquiry may lead us to a better understanding of how to treat and cure this serious disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0242-y) contains supplementary material, which is available to authorized users.

Expression of the oncofetal protein IGF2BP3 in endometrial clear cell carcinoma: assessment of frequency and significance

Insulin-like growth factor-II messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms including ovarian clear cell carcinoma (CCC). In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial CCCs. Cases with scores of 0 to 100, 101 to 200, and 201 to 300 were classified as negative/mildly positive (n = 17), moderately positive (n = 20), and strongly positive (n = 13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (P = .01). Increasing levels of IMP3 expression showed a trend toward decreasing relapse-free survival (RFS; median survival, 75.6, 81.3, and 48.4 months for the negative/mildly, moderately, and strongly positive groups, respectively [P = .09]). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend toward reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggest that IMP3 expression may be involved in the pathogenesis of CCC and is worthy of further exploration.

Modulation of estrogenic action in clear cell carcinoma of the ovary (Review)

Two histologic types, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC), are the common histology in ovarian cancer patients who have associated endometriosis. However, both tumor types have distinct clinicopathological characteristics and molecular phenotypes. EAC is predominantly positive for estrogen receptor (ER), but CCC specifically exhibits lower ER expression. This study reviews the current understanding of the role of the ER information in the pathogenesis of CCC, as well as the English language literature for biochemical studies on ER expression and estrogenic action in CCC. The iron-mediated oxidative stress occurs due to repeated hemorrhage in endometriosis, then this compound oxidatively modifies genomic DNA and, subsequently, ER depletion may be observed. There are a number of factors that interfere with ER expression and estrogen activity, which include DNA methylation of the promoter region, histone deacetylation, heme and iron binding, chromatin remodeling and ubiquitin ligase activity. Loss of estrogen function may be a turning point in CCC progression and aggressiveness.

Redox-Active Iron-Induced Oxidative Stress in the Pathogenesis of Clear Cell Carcinoma of the Ovary

Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic cancer. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) of the ovary have been associated with endometriosis, thus indicating that endometriosis has been believed to increase the risk of developing EOC. The aim of our review was to identify and synthesize the most current information on CCC with regard to molecular and pathophysiological distinctions. This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC carcinogenesis. The iron-induced reactive oxygen species signals can contribute to carcinogenesis via 3 major processes: step 1, by increasing oxidative stress, which promotes DNA mutagenesis, histone modification, chromatin remodeling, and gene products activation/inactivation thus contributing to EAOC initiation; step 2, by activating detoxification and antiapoptotic pathways via the transcription factor hepatocyte nuclear factor 1β overexpression, thereby contributing to CCC promotion; and step 3, by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of cancer cells via estrogen-dependent (EAC) or estrogen-independent (CCC) mechanisms, thus supporting tumor progression and metastasis. These aspects of reactive oxygen species biology will be discussed in the context of its relationship to EAOC carcinogenesis.

Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab.

The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.

The Role of Hepatocyte Nuclear Factor-1β in the Pathogenesis of Clear Cell Carcinoma of the Ovary

Clear cell carcinoma (CCC) of the ovary has a number of features distinguishing it from other epithelial ovarian carcinomas (EOC) because of its characteristic histology and biology, frequent concurrence with endometriotic lesion, and highly chemoresistant nature resulting in an extremely poor prognosis. The incidence of CCC has been steadily increasing in Japan. They comprise approximately 20% of all EOC. Understanding the mechanisms of CCC development and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for CCC. This article reviews the English language literature for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Several data are discussed in the context of endometriosis and CCC biology. Recent studies based on genome-wide expression analysis technology have noted specific expression of hepatocyte nuclear factor-1beta (HNF-1beta) in endometriosis and CCC, suggesting that early differentiation into the clear cell lineage takes place in the endometriosis. The HNF-1beta-dependent pathway of CCC will be discussed, which are providing new insights into regulation of apoptosis and glycogen synthesis and resistance of CCC to anticancer agents. This review summarizes recent advances in the HNF-1beta and its target genes; the potential challenges to the understanding of carcinogenesis, pathogenesis, and pathophysiology of CCC; and a possible novel model is proposed.

New therapies in renal cell carcinoma

We present an update on the dramatic changes that have occurred over the past year in the management of patients with metastatic renal cell carcinoma. Although it was demonstrated that benefit from immunotherapy is restricted to a minority of patients, a better understanding of the molecular mechanisms involved in the pathogenesis of clear cell carcinoma has led to development of multiple targeted therapies, with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of vascular endothelial growth factor receptor have been demonstrated to improve the progression-free survival of patients as first-line (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, which inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor risk characteristics. Finally, bevacizumab combined with interferon is yielding substantial response rates and increased progression-free survival compared with interferon alone. Four major drugs or regimens with proven efficacy are now available for first-line and second-line therapy in metastatic renal cell carcinoma. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.

Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression

This study was designed to analyze certain clinicopathological features and the profile of p53, Ki-67, estrogen (ER), and progesterone (PR) receptor expression of clear cell carcinoma of the endometrium and to determine whether the pathogenesis of clear cell carcinoma can be accommodated by a dualistic model of endometrial carcinogenesis. In this model, endometrioid carcinoma develops from endometrial hyperplasia under unopposed estrogenic stimulation, and serous carcinoma develops in atrophic endometrium from a putative precursor lesion designated endometrial intraepithelial carcinoma (EIC). Twenty-one clear cell carcinomas of the endometrium were analyzed and compared with 77 endometrioid carcinomas of all grades and 30 serous carcinomas. Clear cell carcinomas showed a distinctive immunoprofile characterized by immunonegativity for ER and PR, low immunoreactivity for p53, and a high Ki-67 proliferation index. ER, PR, and Ki-67 expression were similar to serous carcinoma, but p53 expression was significantly lower in clear cell carcinoma (P < .05). ER and PR expression were significantly lower, and the Ki-67 proliferation index was significantly higher in clear cell carcinoma compared with endometrioid carcinomas (P < .05). p53 expression tended to be higher in clear cell carcinoma compared with endometrioid carcinoma, but the difference was not statistically significant. In contrast to endometrioid carcinoma, clear cell carcinoma was rarely associated with endometrial hyperplasia and serous carcinoma was not. Subdividing clear cell carcinoma morphologically into one that resembled serous carcinoma (clear cell carcinoma with serous features) and another that did not (typical clear cell carcinoma) showed that clear cell carcinoma with serous features had a higher Ki-67 proliferation index than typical clear cell carcinoma, although expression of ER, PR, and p53 were similar. Clear cell carcinoma with serous features was associated with EIC in 50% and was not associated with endometrial hyperplasia. In contrast, typical clear cell carcinoma was associated with endometrial hyperplasia in 40% and was not associated with EIC. In summary, this study provides evidence that clear cell carcinoma of the endometrium, like serous carcinoma, is estrogen independent and shows a high Ki-67 proliferation index. In contrast to serous carcinoma, strong p53 expression occurred less frequently in clear cell carcinoma and predominantly in clear cell carcinoma with serous features. The findings suggest that the molecular events that underlie the development of clear cell carcinoma differ from those of endometrioid and serous carcinoma.