Kallikrein family proteases KLK6 and KLK7 are potential early detection and diagnostic biomarkers for serous and papillary serous ovarian cancer subtypes

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Early detection of ovarian cancer remains a challenge due to widespread metastases and a lack of biomarkers for early-stage disease. This study was conducted to identify relevant biomarkers for both laparoscopic and serum diagnostics in ovarian cancer.

Methods

Bioinformatics analysis and expression screening in ovarian cancer cell lines were employed. Selected biomarkers were further validated in bio-specimens of diverse cancer types and ovarian cancer subtypes. For non-invasive detection, biomarker proteins were evaluated in serum samples from ovarian cancer patients.

Results

Two kallikrein (KLK) serine protease family members (KLK6 and KLK7) were found to be significantly overexpressed relative to normal controls in most of the ovarian cancer cell lines examined. Overexpression of KLK6 and KLK7 mRNA was specific to ovarian cancer, in particular to serous and papillary serous subtypes. In situ hybridization and histopathology further confirmed significantly elevated levels of KLK6 and KLK7 mRNA and proteins in tissue epithelium and a lack of expression in neighboring stroma. Lastly, KLK6 and KLK7 protein levels were significantly elevated in serum samples from serous and papillary serous subtypes in the early stages of ovarian cancer, and therefore could potentially decrease the high “false negative” rates found in the same patients with the common ovarian cancer biomarkers human epididymis protein 4 (HE4) and cancer antigen 125 (CA-125).

Conclusion

KLK6 and KLK7 mRNA and protein overexpression is directly associated with early-stage ovarian tumors and can be measured in patient tissue and serum samples. Assays based on KLK6 and KLK7 expression may provide specific and sensitive information for early detection of ovarian cancer.

Electronic supplementary material

The online version of this article (doi:10.1186/s13048-014-0109-z) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 71

Record: found
Abstract: found
Article: not found

High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis.

A K Godwin, A MEISTER, P O'Dwyer … (1992)

Exposure of human ovarian tumor cell lines to cisplatin led to development of cell lines that exhibited increasing degrees of drug resistance, which were closely correlated with increase of the levels of cellular glutathione. Cell lines were obtained that showed 30- to 1000-fold increases in resistance; these cells also had strikingly increased (13- to 50-fold) levels of glutathione as compared with the drug-sensitive cells of origin. These levels of resistance to cisplatin and the cellular glutathione levels are substantially greater than previously reported. Very high cisplatin resistance was associated with enhanced expression of mRNAs for gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase; immunoblots showed increase of gamma-glutamylcysteine synthetase but not of glutathione synthetase. Glutathione S-transferase activity was unaffected, as determined with chlorodinitrobenzene as a substrate. These studies suggest the potential value of examining regulation of glutathione synthesis as an indicator of clinical prognosis. The highly resistant cell lines are proving useful for studying the multiple mechanisms by which tumor cells acquire drug- and radiation-resistance.

0 comments Cited 171 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.

W. McCluggage (2011)

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.

0 comments Cited 136 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Early events in the pathogenesis of epithelial ovarian cancer.

Michael Birrer, Charles N. Landen, Anil Sood (2008)

Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great deal has been learned about proteins and pathways important in the early stages of malignant transformation and metastasis, as derived from studies of individual tumors, microarray data, animal models, and inherited disorders that confer susceptibility. However, a full understanding of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lack of a well-defined premalignant state common to all ovarian subtypes and by the paucity of data from early-stage cancers. Evidence suggests that ovarian cancers can progress both through a stepwise mutation process (low-grade pathway) and through greater genetic instability that leads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In this review, we discuss many of the genetic and molecular disorders in each key process that is altered in cancer cells, and we present a model of ovarian pathogenesis that incorporates the role of tumor cell mutations and factors in the host microenvironment important to tumor initiation and progression.

0 comments Cited 120 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Ayala Tamir: ATamir@HackensackUMC.org

Ushma Jag: Ujag@humed.com

Sreeja Sarojini: SSarojini@HackensackUMC.org

Craig Schindewolf: CSchindewolf@HackensackUMC.org

Takemi Tanaka: takemi.tanaka@ouhsc.edu

Rajendra Gharbaran: RGharbaran@HackensackUMC.org

Hiren Patel: HPatel@humed.com

Anil Sood: asood@mdanderson.org

Wei Hu: whu@mdanderson.org

Ruzeen Patwa: RPatwa@humed.com

Patrick Blake: pat@sophicalliance.com

Polina Chirina: Pchirina@HackensackUMC.org

Jin Oh Jeong: pokey0099@gmail.com

Heejin Lim: Heejinlim223@gmail.com

Andre Goy: AGoy@HackensackUMC.org

Andrew Pecora: APecora@HackensackUMC.org

K Stephen Suh: KSuh@HackensackUMC.org

Journal

Journal ID (nlm-ta): J Ovarian Res

Journal ID (iso-abbrev): J Ovarian Res

Title: Journal of Ovarian Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-2215

Publication date (Electronic): 5 December 2014

Publication date PMC-release: 5 December 2014

Publication date Collection: 2014

Volume: 7

Issue: 1

Electronic Location Identifier: 109

Affiliations

[ ]The Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, D. Jurist Research Building, 40 Prospect Avenue, Hackensack, NJ 07601 USA

[ ]Thomas Jefferson University, Philadelphia, PA 19107 USA

[ ]Departments of Gynecologic Oncology and Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030 USA

[ ]Sophic Systems Alliance, Inc, Rockville, MD 20850 USA

Article

Publisher ID: 109

DOI: 10.1186/s13048-014-0109-z

PMC ID: 4271347

PubMed ID: 25477184

SO-VID: 2f31aae0-abab-4e37-bfc9-305b92d95dc8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 March 2014

Date accepted : 11 November 2014

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: biomarker,ovarian cancer,diagnostic,early detection,bioinformatics

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: biomarker, ovarian cancer, diagnostic, early detection, bioinformatics

Kallikrein family proteases KLK6 and KLK7 are potential early detection and diagnostic biomarkers for serous and papillary serous ovarian cancer subtypes

Read this article at

Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 71

High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis.

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.

Early events in the pathogenesis of epithelial ovarian cancer.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 364

Cited by 13

Most referenced authors 619