To evaluate the expression (nuclear and cytoplasmatic) of PTOV1 , Notch and Wnt on TMAs in c different histological types of carcinomas with low and high grades of malignancy  . To correlate the inmunoexpression with classical parameters of  tumor behaviour : tumoral size, grade of malignancy, vascular permeation, lymph nodes metastasis in each histological subtype and demonstrated the role of PTOV1 as predictive molecular marker in carcinomas.

(Research Biomedical Unit)

We have postulated that hHAVcr-1 might constitute an important biomarker for early detection of ccRCC and could also be used as a target for therapy of kidney carcinomas, since immunotoxins directed against the monkey homologue of hHAVcr-1 could kill kidney cells.

Specific aims are focused to: i) determine the diagnostic and prognostic potential of hHAVcr-1 expression in renal cell carcinomas, by correlating hHAVcr-1 levels in archive, fresh surgical and TMA tissues  with tumor anatomo-pathological characteristics and patients outcome and, ii) determine the function of hHAVcr-1, which remains elusive, in development and progression of kidney carcinomas, using ccRCC derived cell lines with silenced or overexpressed hHAVcr-1. Tumors overexpressing or defective in hHAVcr-1 will be compared with controls, in relation to their behavior and anatomo-pathological characteristics. Differences are being correlated with proteomic and gene expression profiles obtained on each case. Differential expression pathways and target molecules correlating with absence/presence of hHAVcr-1 shall be identified. New strategies for diagnosis, prognosis and treatment of ccRCC must be further developed.

(Programa de Recerca en Cancer Renal CIBBIM-IRHUVH. )

Group Leaders

Jaume Reventós

Anna Ruiz,

Antonio Gil

Principal Investigators

Jaume Reventós (MD, PhD)

Anna Ruiz (PhD)

Antonio Gil (MD)

Jordi Xercavins (MD, PhD)

Research Team

Marta Llauradó (Graduate Student)

Eva Colás (Graduate Student)

Núria Pedrola (Graduate Student)

Sílvia Cabrera (Clinical Associated Investigator)

Assumpció Pérez (Clinical Associated Investigator)

Research Focus

We are focused on the understanding of the molecular bases of endometrial and ovarian cancers. In particular, in new molecules involved in progression and dissemination. Our search also includes new molecular biomarkers of precocious diagnosis as well as molecular therapeutic targets.

Research Lines in Endometrial Cancer (EC)

Differential gene expression in endometrial cancer: analysis of the roles of transcription factors Runx1 and ETV5 in the progression and dissemination of tumors

Previous research in our lab has identifi ed ETV5 and RUNX1 proteins as key determinants of myometrial invasion and dissemination. The main objective of the project is the investigation of the molecular mechanisms regulated by the ETV5 and RUNX1 transcription factors that are responsible for endometrial cancer cell invasion and dissemination. To achieve these objectives we have already developed some tools such as endometrial cancer cell lines with ETV5 overexpression or downregulation. The identifi cation of proteins involved in the invasion and dissemination processes will lead to the design of new experimental therapies that will be evaluated (tumor growth, metastasis) in the orthotopic animal models that we have developed for endometrial cancer.

Development of highly-sensitive and highly-efficient molecular tools for the diagnosis of endometrial cancer in uterine aspirates

Through a proteomic approach, our lab has identifi ed and validated new robust biomarkers for endometrial carcinoma using human samples obtained from uterine aspirates. Our objective is to develop a reliable tool for screening EC risk using endometrial biopsies, which will enhance sensitivity and specificity, as well as preclude unnecessary hysteroscopy.

Development of endometrial orthotopic murine models to test new therapies

We have developed two different orthotopic endometrial cancer murine models that might be useful tools in endometrial cancer preclinical studies. The generation of these murine models for endometrial cancer has been achieved by inoculation of either a tumor cell line or human tumor tissue intra-uterus.The Hec-1A endometrial cancer cell line derived model represents advanced disease and can be used to test the effi cacy of antimetastastic drugs. In this model, the follow-up of disease progression is performed using bioluminescence in vivo and correlating bioluminescence ex vivo with metastasis generation. The human tissue derived model maintains the histological pattern and represents local and locally-advanced disease, and can be used to test drugs against specific targets of endometrial cancer.

Characterization by proteomics and genomics of markers expressed differentially at the EC invasion front and in metastasis

Using an orthotopic mouse model we have shown the involvement of RUNX1 in distant metastasis in endometrial cancer. Using proteomics, we have also shown a series of promising proteins involved in myometrial invasion that are differently expressed between cancer and age-matched uterine tissue. Our goal is to identify the gene clusters involved in invasion and metastasis and to study their therapeutic potential using preclinical mouse models.

Research Lines in Ovarian Cancer (OC)

New biomarker identifi cation for ovarian cancer diagnosis, prognosis and drug treatment

This project proposes the identification of new molecular biomarkers for the diagnosis and prognosis of ovarian cancer. Microarray technology has been used to identify molecules differentially expressed between tumoral tissue and control samples. The fi nal goal is to identify a panel of biomarkers that can distinguish the presence or absence of ovarian cancer.

Mechanisms of cancer cell dissemination regulated by ETV5 in ovarian cancer

Previous research in our lab has identifi ed ETV5 as a protein overexpressed in ovarian cancer. We have characterized its role in ovarian tumour progression. Currently, we are characterizing ETV5 target genes involved in ovarian cancer dissemination through the peritoneal cavity. The fi nal goal is to design new therapies to stop ovarian cancer cell dissemination.

Molecular pathways involved in ovarian cancer cell dissemination

Ovarian cancer disseminates to secondary sites through the peritoneal cavity. Ovarian cancer cells are shed from the ovarian primary tumor, aggregate as spheroids within the abdominal cavity and subsequently attach to the peritoneal wall. We are interested in the identifi cation of those molecular pathways involved in ovarian cell dissemination through the peritoneal cavity in order to design new therapies that target ovarian cancer dissemination and therefore ovarian cancer spread to secondary sites.

Cohort study comparing surgical vs laparoscopic staging and treatment in primary endometrial cancer (clinical stage I)

Other Clinical Research Projects

• Prospective study of validation of sentinel lymph node detection technique in cervical cancer in initial stages.

• Prospective study of validation of sentinel lymph node detection technique in vulvar cancer in initial stages.

• Prospective comparative study of laparoscopic versus laparotomic radical hysterectomy approach in initial cervical cancer treatment.

• Prospective study of validation of extra-peritoneal aortic laparoscopic or robotic assisted lymphadenectomy in locally advanced or bulky cervical cancer.

• Prospective comparative study of robotic assisted versus laparoscopic versus laparotomic approaches in endometrial cancer (supported by AATRM, Technology and Medical Research Evaluation Agency).

• Pre-neoplasic vaginal and vulvar pathology: VIN and VAIN.

• Study of p-16 as a progression marker in cervical pre-invasive lesions.

• Follow-up in women with HPV 16 infection.

• CIN and pregnancy.

• Follow-up of women treated for H-SIL cervical cancer lesions.

• Endocervical sample as a marker of relapse in cervical intraepithelial neoplasia.

• Results of neo-adjuvant concomitant chemo-radiotherapy in the treatment of locally advanced cervical cancer.

• Validation of robotic assisted and laparoscopic aortic extraperitoneal lymphadenectomy in recurrences of gynaecologic malignancies.

• Evaluation of robotic surgery in the treatment of gynaecologic malignancies.

• Borderline ovarian tumours.

• Endoscopic treatment of ovarian cancer in initial stages.

• Ressecability predictive value of laparoscopic approach in advanced ovarian cancer.

• Results of neo-adjuvant chemotherapy in the treatment of advanced ovarian cancer.

All the above strategies leading to the discovery of new biomarkers, are validated in specifically designed tissue microarrays using immuno-histochemistry in FFPE samples from radical prostatectomies.