Molecular profiling of cervical cancer progression

Most cancer patients die of metastatic or recurrent disease, hence the importance to identify target genes upregulated in these lesions. Although a variety of gene signatures associated with metastasis or poor prognosis have been identified in various cancer types, it remains a critical problem to identify key genes as candidate therapeutic targets in metastatic or recurrent cancer. The aim of our study was to identify genes consistently upregulated in both lymph node micrometastases and recurrent tumours compared to matched primary tumours in human cervical cancer. Taqman Low-Density Arrays were used to analyse matched tumour samples, obtained after laser-capture microdissection of tumour cell islands for the expression of 96 genes known to be involved in tumour progression. Immunohistochemistry was performed for a panel of up- and downregulated genes. In lymph node micrometastases, most genes were downregulated or showed expressions equal to the levels found in primary tumours. In more than 50% of lymph node micrometastases studied, eight genes (AKT, BCL2, CSFR1, EGFR1, FGF1, MMP3, MMP9 and TGF-β) were upregulated at least two-fold. Some of these genes (AKT and MMP3) are key regulators of epithelial–mesenchymal transition in cancer. In recurrent tumours, almost all genes were upregulated when compared to the expression profiles of the matched primary tumours, possibly reflecting their aggressive biological behaviour. The two genes showing a consistent downregulated expression in almost all lymph node metastases and recurrent tumours were BAX and APC. As treatment strategies are very limited for metastatic and recurrent cervical cancer, the upregulated genes identified in this study are potential targets for new molecular treatment strategies in metastatic or recurrent cervical cancer.

[1]  H. Höfler,et al.  Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue. , 2001, The American journal of pathology.

[2]  Wei Zhang,et al.  Profiling of differentially expressed genes in human primary cervical cancer by complementary DNA expression array. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  S. Syrjänen,et al.  Transcriptional profiling of a human papillomavirus 33–positive squamous epithelial cell line which acquired a selective growth advantage after viral integration , 2002, International journal of cancer.

[4]  E. Kubista,et al.  cDNA array analysis of cytobrush-collected normal and malignant cervical epithelial cells: a feasibility study. , 2005, Cancer genetics and cytogenetics.

[5]  R. Nagle,et al.  Fibroblast growth factor‐1 transcriptionally induces membrane type‐1 matrix metalloproteinase expression in prostate carcinoma cell line , 2004, The Prostate.

[6]  Philip Lijnzaad,et al.  An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas , 2005, Nature Genetics.

[7]  Wenbiao Liu,et al.  Expression of epidermal growth factor receptor and human papillomavirus E6/E7 proteins in cervical carcinoma cells. , 1997, Journal of the National Cancer Institute.

[8]  J. Peto,et al.  Human papillomavirus is a necessary cause of invasive cervical cancer worldwide , 1999, The Journal of pathology.

[9]  José A García,et al.  Overexpression of cathepsin f, matrix metalloproteinases 11 and 12 in cervical cancer , 2005, BMC Cancer.

[10]  Mads Hald Andersen,et al.  Regulators of apoptosis: suitable targets for immune therapy of cancer , 2005, Nature Reviews Drug Discovery.

[11]  C. Rosales,et al.  R-Ras promotes metastasis of cervical cancer epithelial cells , 2007, Cancer Immunology, Immunotherapy.

[12]  K. Pantel,et al.  Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. , 1991, Cancer research.

[13]  I. Jacobs,et al.  A model for co-expression pattern analysis of genes implicated in angiogenesis and tumour cell invasion in cervical cancer , 2002, British Journal of Cancer.

[14]  Susan Andrea Gutiérrez Rubio,et al.  EcoRI polymorphism of the metastasis-suppressor gene NME1 in Mexican patients with breast cancer , 2006, Breast Cancer Research and Treatment.

[15]  J. Kim,et al.  Prognostic value of activated Akt expression in oral squamous cell carcinoma , 2005, Journal of Clinical Pathology.

[16]  A. Chinnaiyan,et al.  Bioinformatics Strategies for Translating Genome‐Wide Expression Analyses into Clinically Useful Cancer Markers , 2004, Annals of the New York Academy of Sciences.

[17]  D. Koller,et al.  A module map showing conditional activity of expression modules in cancer , 2004, Nature Genetics.

[18]  Erik Sahai,et al.  Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. , 2005, Cancer research.

[19]  L. Coussens,et al.  MMP9 potentiates pulmonary metastasis formation. , 2002, Cancer cell.

[20]  Gerard C Blobe,et al.  Role of transforming growth factor Beta in human cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  C. Arteaga,et al.  TGFbeta1 -mediated epithelial to mesenchymal transition is accompanied by invasion in the SiHa cell line. , 2002, European journal of cell biology.

[22]  L. Chodosh,et al.  Conditional Overexpression of Active Transforming Growth Factor β1 In vivo Accelerates Metastases of Transgenic Mammary Tumors , 2004, Cancer Research.

[23]  Yoram Cohen,et al.  Detecting cervical cancer by quantitative promoter hypermethylation assay on cervical scrapings: a feasibility study. , 2004, Molecular cancer research : MCR.

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

[25]  George Stoica,et al.  Expression of MMP2, MMP9 and MMP3 in Breast Cancer Brain Metastasis in a Rat Model , 2005, Clinical & Experimental Metastasis.

[26]  Alfonso Bellacosa,et al.  Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways , 2005, Oncogene.

[27]  I. Stamenkovic,et al.  Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival , 2004, Clinical & Experimental Metastasis.

[28]  C. Woodworth,et al.  Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment , 2005, Molecular Cancer Therapeutics.

[29]  C. Gilles,et al.  GM-CSF expression by tumor cells correlates with aggressivity and with stroma reaction formation. , 2000, Journal of submicroscopic cytology and pathology.

[30]  R. Guo,et al.  Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. , 2006, Lung cancer.

[31]  Peter Schow,et al.  Tumor-cell resistance to death receptor–induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax , 2002, Nature Medicine.

[32]  H. Hausen.  Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[33]  E. Lander,et al.  A molecular signature of metastasis in primary solid tumors , 2003, Nature Genetics.

[34]  M. Ittmann,et al.  The role of fibroblast growth factors and their receptors in prostate cancer. , 2004, Endocrine-related cancer.

[35]  Tak-Hong Cheung,et al.  Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  Harald zur Hausen,et al.  Papillomaviruses Causing Cancer: Evasion From Host-Cell Control in Early Events in Carcinogenesis , 2000 .

[37]  D. Albertson,et al.  Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability , 2005, Nature.

[38]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[39]  S. Krüger,et al.  Inhibition of bcl-2 enhances the efficacy of chemotherapy in renal cell carcinoma. , 2005, European urology.

[40]  M. Shibuya,et al.  Tumorigenicity depends on angiogenic potential of tumor cells: dominant role of vascular endothelial growth factor and/or fibroblast growth factors produced by tumor cells , 2004, Angiogenesis.

[41]  S. Zucker,et al.  Role of matrix metalloproteinases (MMPs) in colorectal cancer , 2004, Cancer and Metastasis Reviews.

[42]  S. Kloeker,et al.  TGF-beta inhibitors for the treatment of cancer. , 2005, Expert opinion on investigational drugs.

[43]  S. Kloeker,et al.  TGF-β inhibitors for the treatment of cancer , 2005 .

[44]  S. Fujieda,et al.  Reliability of platelet-derived endothelial cell growth factor as a prognostic factor for oral and oropharyngeal carcinomas. , 2005, Archives of otolaryngology--head & neck surgery.

[45]  W. Sellers,et al.  Overexpression, Amplification, and Androgen Regulation of TPD52 in Prostate Cancer , 2004, Cancer Research.

[46]  José A García,et al.  Gene identification by cDNA arrays in HPV-positive cervical cancer. , 2005, Archives of medical research.

[47]  D. Spandidos,et al.  Transcriptional inactivation of p53, Bax, Bcl-2 and Mdm2 correlates with malignant transformation of the uterine cervix. , 2005, The International journal of biological markers.