Candidate biomarkers for cervical cancer treatment: Potential for clinical practice (Review).

Cervical cancer ranks high among the causes of female cancer mortalities and is an important disease in developing and developed countries. Current diagnosis of cervical cancer depends on colposcopy, pathological diagnosis and preoperative diagnosis using methods, including magnetic resonance imaging and computed tomography. Advanced cervical cancer has a poor prognosis. The tumor marker squamous cell carcinoma is conventionally used for screening, but recent studies have revealed the mechanisms of carcinogenesis and the factors associated with a poor prognosis in cervical cancer. These include epigenetic biomarkers, with the methylation level of the checkpoint with forkhead and ring finger gene being potentially useful for predicting the malignancy of cervical cancer and sensitivity to treatment with paclitaxel. The extent of methylation of the Werner DNA helicase gene is also useful for determining sensitivity to an anticancer agent, CPT-11. In addition to epigenetic changes, the expression levels of hypoxia-inducible factor 1α subunit, epidermal growth factor receptor and cyclooxygenase-2 have been reported as possible biomarkers in cervical cancer. Novel prognostic factors, including angiogenic factors, fragile histidine triad, thymidylate synthase, glucose-related protein 58 and mucin antigens, have also been described, and hemoglobin and platelets may also be significant prognostic biomarkers. Utilization of these biomarkers may facilitate personalized treatment and improved outcomes in cervical cancer.

[1]  V. Bohr,et al.  Functional deficit associated with a missense Werner syndrome mutation. , 2013, DNA repair.

[2]  A. Gadducci,et al.  Tissue biomarkers as prognostic variables of cervical cancer. , 2013, Critical reviews in oncology/hematology.

[3]  G. Qian,et al.  Hypoxia inducible factor‐1α‐mediated activation of survivin in cervical cancer cells , 2013, The journal of obstetrics and gynaecology research.

[4]  Lijun Zhao,et al.  Histone deacetylase inhibitors inducing human cervical cancer cell apoptosis by decreasing DNA-methyltransferase 3B. , 2012, Chinese Medical Journal.

[5]  D. Aoki,et al.  Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells , 2012, Oncology reports.

[6]  F. M. Yeong,et al.  CHFR: a key checkpoint component implicated in a wide range of cancers , 2012, Cellular and Molecular Life Sciences.

[7]  S. H. van der Burg,et al.  CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients , 2012, British Journal of Cancer.

[8]  H. Liu,et al.  Celecoxib Radiosensitizes the Human Cervical Cancer HeLa Cell Line via a Mechanism Dependent on Reduced Cyclo-Oxygenase-2 and Vascular Endothelial Growth Factor C Expression , 2012, The Journal of international medical research.

[9]  Ying Liang,et al.  Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer , 2011, Cancer science.

[10]  Y. Zhang,et al.  Effects of DNMT1 silencing on malignant phenotype and methylated gene expression in cervical cancer cells , 2011, Journal of experimental & clinical cancer research : CR.

[11]  N. Joste,et al.  Epidermal growth factor receptor as a biomarker for cervical cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  P. Jagodziński,et al.  Transcriptional analysis of CXCR4, DNMT3A, DNMT3B and DNMT1 gene expression in primary advanced uterine cervical carcinoma. , 2011, International journal of oncology.

[13]  M. Holden,et al.  Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer , 2011, Clinical Cancer Research.

[14]  S. Yeasmin,et al.  EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target , 2011, British Journal of Cancer.

[15]  S. Steinberg,et al.  Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors , 2011, Clinical Cancer Research.

[16]  E. Schuuring,et al.  Prognostic cell biological markers in cervical cancer patients primarily treated with (chemo)radiation: a systematic review. , 2011, International journal of radiation oncology, biology, physics.

[17]  Shulan Zhang,et al.  Clinical significance of serum Dkk‐3 in patients with gynecological cancer , 2010, The journal of obstetrics and gynaecology research.

[18]  B. Monk,et al.  Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Shiying Yu,et al.  Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells. , 2010, Cancer biotherapy & radiopharmaceuticals.

[20]  S. Chichareon,et al.  Correlation of p53 and Ki‐67 (MIB‐1) expressions with clinicopathological features and prognosis of early stage cervical squamous cell carcinomas , 2010, The journal of obstetrics and gynaecology research.

[21]  S. Batra,et al.  Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix , 2010, The journal of obstetrics and gynaecology research.

[22]  Takehiko Koji,et al.  Human Papillomavirus Infection and Its Possible Correlation with p63 Expression in Cervical Cancer in Japan, Mongolia, and Myanmar , 2009, Acta histochemica et cytochemica.

[23]  H. Hollema,et al.  Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer , 2009, Clinical Cancer Research.

[24]  P. Michieli.  Hypoxia, angiogenesis and cancer therapy: To breathe or not to breathe? , 2009, Cell cycle.

[25]  M. Raica,et al.  Characterization of endoglin and Ki‐67 expression in endothelial cells from benign and malignant lesions of the uterine cervix , 2009, Pathology international.

[26]  K. Ushijima.  Current status of gynecologic cancer in Japan. , 2009, Journal of gynecologic oncology.

[27]  T. Sano,et al.  Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. , 2008, The journal of medical investigation : JMI.

[28]  C. Tzeng,et al.  Roles for hypoxia-regulated genes during cervical carcinogenesis: somatic evolution during the hypoxia-glycolysis-acidosis sequence. , 2008, Gynecologic oncology.

[29]  D. Aoki,et al.  Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes. , 2007, International journal of oncology.

[30]  A. Shimamoto,et al.  Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase. , 2007, Biological & pharmaceutical bulletin.

[31]  R. Johnson,et al.  Hypoxia: A key regulator of angiogenesis in cancer , 2007, Cancer and Metastasis Reviews.

[32]  T. Osaki,et al.  The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells , 2007 .

[33]  Suzuyo Takahashi,et al.  [Prognostic factors of uterine cervical cancer]. , 2006, Gan to kagaku ryoho. Cancer & chemotherapy.

[34]  H. Chung,et al.  XRCC1 R399Q polymorphism is associated with response to platinum-based neoadjuvant chemotherapy in bulky cervical cancer. , 2006, Gynecologic oncology.

[35]  H. Kuwano,et al.  Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. , 2006, Oncology reports.

[36]  M. Fraga,et al.  Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S. Hirohashi,et al.  DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. , 2006, Carcinogenesis.

[38]  K. Ang,et al.  Inhibition of DNA repair as a mechanism of enhanced radioresponse of head and neck carcinoma cells by a selective cyclooxygenase-2 inhibitor, celecoxib. , 2005, International journal of radiation oncology, biology, physics.

[39]  V. Hebbar,et al.  Chance mechanisms affecting the burden of metastases , 2005, BMC Cancer.

[40]  A. Lopes,et al.  Comparison of pre-treatment CYFRA 21 – 1 and SCC-Antigen assay in primary cervical carcinoma – a preliminary report , 2005, Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology.

[41]  H. Lane,et al.  ERBB receptors and cancer: the complexity of targeted inhibitors , 2005, Nature Reviews Cancer.

[42]  M. Ichihara,et al.  CD109 expression in squamous cell carcinoma of the uterine cervix , 2005, Pathology international.

[43]  A. Harris,et al.  Hypoxia-Inducible Factor 1α Expression as an Intrinsic Marker of Hypoxia , 2004, Clinical Cancer Research.

[44]  K. Keum,et al.  Differential cyclooxygenase-2 expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. , 2004, International journal of radiation oncology, biology, physics.

[45]  Peter Vaupel,et al.  Tumor microenvironmental physiology and its implications for radiation oncology. , 2004, Seminars in radiation oncology.

[46]  E. Martinelli,et al.  Prognostic Role of the Ratio between Cyclooxygenase-2 in Tumor and Stroma Compartments in Cervical Cancer , 2004, Clinical Cancer Research.

[47]  M. Gassmann,et al.  HIFs and tumors--causes and consequences. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[48]  K. Ang,et al.  Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. , 2004, International journal of radiation oncology, biology, physics.

[49]  J. Lee,et al.  Synchronous Coexpression of Epidermal Growth Factor Receptor and Cyclooxygenase-2 in Carcinomas of the Uterine Cervix , 2004, Clinical Cancer Research.

[50]  Y. Pommier,et al.  Topoisomerase I-Mediated Inhibition of Hypoxia-Inducible Factor 1 , 2004, Cancer Research.

[51]  R. Shoemaker,et al.  Targeting Topoisomerase 1 to inhibit Hypoxia Inducible Factor 1 , 2004, Cell cycle.

[52]  K Kian Ang,et al.  The epidermal growth factor receptor mediates radioresistance. , 2003, International journal of radiation oncology, biology, physics.

[53]  Y. Saga,et al.  Abnormal Fragile Histidine Triad Expression in Advanced Cervical Cancer and Evaluation of Its Utility as a Prognostic Factor , 2003, Oncology.

[54]  K. Subbaramaiah,et al.  The overexpression of cyclo-oxygenase-2 in chronic periodontitis. , 2003, Journal of the American Dental Association.

[55]  L. Mazzucchelli,et al.  Significant correlation of hypoxia-inducible factor-1alpha with treatment outcome in cervical cancer treated with radical radiotherapy. , 2003, International journal of radiation oncology, biology, physics.

[56]  R. Pötter,et al.  Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[57]  D. Scudiero,et al.  Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. , 2002, Cancer research.

[58]  K. Alitalo,et al.  Vascular growth factors and lymphangiogenesis. , 2002, Physiological reviews.

[59]  Rajnish A. Gupta,et al.  Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 , 2001, Nature Reviews Cancer.

[60]  A. Hongo,et al.  Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer , 2001, British Journal of Cancer.

[61]  P Vaupel,et al.  Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. , 2001, Seminars in oncology.

[62]  G. Thomas.  The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience. , 2001, Seminars in oncology.

[63]  Fan Zhang,et al.  Cyclooxygenase-2 is overexpressed in human cervical cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[64]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[65]  A. Harris,et al.  Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. , 2000, Cancer research.

[66]  P. Heller,et al.  The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study. , 2000, Gynecologic oncology.

[67]  M. Katori,et al.  Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors , 2000, Inflammation Research.

[68]  S. Tsukagoshi,et al.  Enhanced Expression of Thymidylate Synthase May Be of Prognostic Importance in Advanced Cervical Cancer , 1999, Oncology.

[69]  T. Tamaya,et al.  Clinical implication of expression of platelet-derived endothelial cell growth factor (PD-ECGF) in metastatic lesions of uterine cervical cancers. , 1999, Cancer research.

[70]  A. Hongo,et al.  Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in endometrial cancer. , 1999, International Journal of Oncology.

[71]  M. Dimopoulos,et al.  Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  R. Li,et al.  [Effect of different animal skin on the transdermal speed constant of sinomenine]. , 1998, Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials.

[73]  Y. Hirai,et al.  The value of squamous cell carcinoma antigen as a predictor of nodal metastasis in cervical cancer. , 1998, Gynecologic oncology.

[74]  A. Lopes,et al.  Prognostic value of preoperative squamous cell carcinoma antigen level in patients surgically treated for cervical carcinoma. , 1997, Gynecologic oncology.

[75]  C. Croce,et al.  The FHIT Gene, Spanning the Chromosome 3p14.2 Fragile Site and Renal Carcinoma–Associated t(3;8) Breakpoint, Is Abnormal in Digestive Tract Cancers , 1996, Cell.

[76]  K. Smith-McCune,et al.  Demonstration and characterization of the angiogenic properties of cervical dysplasia. , 1994, Cancer research.

[77]  J. Bourhis,et al.  Human papillomavirus-negative status and c-myc gene overexpression: independent prognostic indicators of distant metastasis for early-stage invasive cervical cancers. , 1992, Journal of the National Cancer Institute.

[78]  T. Iwasaka,et al.  Detection of human papillomavirus genome and analysis of expression of c-myc and Ha-ras oncogenes in invasive cervical carcinomas. , 1992, Gynecologic oncology.

[79]  S. Schneider-Maunoury,et al.  Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogene expression , 1991, Journal of virology.

[80]  S. Pinion,et al.  Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix , 1991, The Lancet.

[81]  M. Yamasaki,et al.  Chromosomal Insertion and Amplification of Human Papillomavirus 16 DNA Sequences in a Cell Line of Argyrophil Small Cell Carcinoma of the Uterine Cervix , 1991, Japanese journal of cancer research : Gann.

[82]  H. Hollema,et al.  Cancer of the uterine cervix: sensitivity and specificity of serum squamous cell carcinoma antigen determinations. , 1990, Gynecologic oncology.

[83]  K. Miyazono,et al.  Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor , 1989, Nature.

[84]  K. Hatch,et al.  Phase II trials of cisplatin and piperazinedione as single agents in the treatment of advanced or recurrent non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. , 1986, Cancer treatment reports.

[85]  T. Maruo,et al.  Tumor‐associated antigen, TA‐4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Serial Determinations and Tissue Localization , 1985, Cancer.

[86]  H. Homesley,et al.  Phase II trial of etoposide in the management of advanced or recurrent non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. , 1984, Cancer treatment reports.

[87]  H. Kato,et al.  Value of tumor‐antigen (TA‐4) of squamous cell carcinoma in predicting the extent of cervical cancer , 1982, Cancer.

[88]  A. Haspels,et al.  Carcinoembryonic antigen serumlevels in patients with squamous cell carcinoma of the uterine cervix: Clinical significance , 1982, Cancer.

[89]  H. Kato,et al.  Radioimmunoassay for tumor-antigen of human cervical squamous cell carcinoma. , 1977, Cellular and molecular biology, including cyto-enzymology.

[90]  S. Landolfo,et al.  Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis. , 2008, Gynecologic oncology.

[91]  T. Osaki,et al.  The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells. , 2007, International journal of cancer.

[92]  A. Maity,et al.  Hypoxia and VEGF mRNA expression in human tumors. , 2001, Neoplasia.

[93]  D. Santini,et al.  CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma. , 2001, Gynecologic oncology.

[94]  Taylor Murray,et al.  Cancer statistics, 2000 , 2000, CA: a cancer journal for clinicians.

[95]  A. Hongo,et al.  Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in cervical cancer. , 1999, International journal of oncology.

[96]  A. Gerbaulet,et al.  Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. , 1989, International journal of radiation oncology, biology, physics.