Expression of metalloproteinases MMP-2 and MMP-9 is associated to the presence of androgen receptor in epithelial ovarian tumors.

BACKGROUND: The current study evaluated the metalloproteinases MMP-2 and MMP-9 expression in epithelial cells and the surrounding stroma in ovarian tumors and the association of MMPs with the histological subtypes, the clinical stage and the presence of steroid hormone receptors. Tumor samples were obtained from 88 patients undergoing surgical cytoreduction of primary ovarian tumors in Instituto Nacional de Cancerología, from México City. The formalin fixed and paraffin embedded samples were processed in order to demonstrate the presence of androgen receptor,estrogen receptor alpha, progesterone receptor, MMP-2,MMP-9 and collagen IV by immunohistochemistry and/or immunofluorescence. RESULTS: MMP-2 and MMP-9 were differentially expressed in the epithelium and the stroma of ovarian tumors associated to histological subtype, clinical stage and sexual steroid hormone receptor expression. Based on Cox proportional hazard regression model we demonstrated that MMP-2 located in the epithelium and the stroma are independent prognostic biomarkers for overall survival in epithelial ovarian tumors. Kaplan Meir analysis of the combination of AR (+) with MMP-2 (+) in epithelium and AR (+) with MMP-2 (-) in stroma displayed a significant reduction of survival. CONCLUSIONS: The presence of MMP-2 in the stroma of the tumor was a protective factor while the presence of MMP-2 in the epithelium indicated an adverse prognosis. The presence of AR associated with MMP-2 in the tumor cells was a risk factor for overall survival in epithelial ovarian cancer.

Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway.

PURPOSE: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. EXPERIMENTAL DESIGN: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. RESULTS: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. CONCLUSIONS: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy.

Splice variants of zinc finger protein 695 mRNA associated to ovarian cancer.

BACKGROUND: Studies of alternative mRNA splicing (AS) in health and disease have yet to yield the complete picture of protein diversity and its role in physiology and pathology. Some forms of cancer appear to be associated to certain alternative mRNA splice variants, but their role in the cancer development and outcome is unclear. METHODS: We examined AS profiles by means of whole genome exon expression microarrays (Affymetrix GeneChip 1.0) in ovarian tumors and ovarian cancer-derived cell lines, compared to healthy ovarian tissue. Alternatively spliced genes expressed predominantly in ovarian tumors and cell lines were confirmed by RT-PCR. RESULTS: Among several significantly overexpressed AS genes in malignant ovarian tumors and ovarian cancer cell lines, the most significant one was that of the zinc finger protein ZNF695, with two previously unknown mRNA splice variants identified in ovarian tumors and cell lines. The identity of ZNF695 AS variants was confirmed by cloning and sequencing of the amplicons obtained from ovarian cancer tissue and cell lines. CONCLUSIONS: Alternative ZNF695 mRNA splicing could be a marker of ovarian cancer with possible implications on its pathogenesis.

Mitosis is a source of potential markers for screening and survival and therapeutic targets in cervical cancer.

The effect of preventive human papillomavirus (HPV) vaccination on the reduction of the cervical cancer (CC) burden will not be known for 30 years. Therefore, it's still necessary to improve the procedures for CC screening and treatment. The objective of this study was to identify and characterize cellular targets that could be considered potential markers for screening or therapeutic targets. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CCs and 12 healthy cervical epitheliums using microarrays. A total of 997 genes were deregulated, and 21 genes that showed the greatest deregulation were validated using qRT-PCR. The 6 most upregulated genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored in 29 low-grade cervical intraepithelial neoplasias (CIN1) and 21 high-grade CIN (CIN2/3) to investigate whether they could differentiate CC and CIN2/3 (CIN2+) from CIN1 and controls. CCNB2, PRC1, and SYCP2 were mostly associated with CC and CDC20, NUSAP1, and CDKN3 were also associated with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1 to detect CIN2+ was approximately 90%. The proteins encoded by all 6 genes were shown upregulated in CC by immunohistochemistry. The association of these markers with survival was investigated in 42 CC patients followed up for at least 42 months. Only CDKN3 was associated with poor survival and it was independent from clinical stage (HR = 5.9, 95%CI = 1.4-23.8, p = 0.01). CDKN3 and NUSAP1 may be potential targets for the development of screening methods. Nevertheless, further studies with larger samples are needed to define the optimal sensitivity and specificity. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be not only a screening and survival marker but a potential therapeutic target in CC. However, whether it's indispensable for tumor growth remains to be demonstrated.

CD3zeta expression and T cell proliferation are inhibited by TGF-beta1 and IL-10 in cervical cancer patients.

INTRODUCTION: Cervical cancer development from a squamous intraepithelial lesion is thought to be favored by an impaired T cell immunity. We evaluated parameters of T cell alterations such as proliferation, cytokine, and CD3zeta expression in peripheral blood and tumor-infiltrating T lymphocytes from women with squamous intraepithelial lesions (SIL) or cervical cancer (CC). RESULTS AND DISCUSSION: T cell proliferation and cytokine messenger RNA (mRNA) expression were similar in women with SIL and healthy donors, whereas low T cell proliferation and lower mRNA expression of IL-2, IL-10 and IFN-gamma were observed in women with CC. Moreover, infiltrating cells showed marginal responses. We also found that CD3zeta mRNA expression, whose protein is required for T cell activation, correlated with a decreased proliferation in advanced stages of the disease. CONCLUSION: Experiments with T cells from healthy donors in the presence TGF-beta1 or IL-10 suggest that these cytokines have a relevant role in T cell responses during CC progression.

Tratamiento del cáncer ovárico / Treatment of ovarian cancer

Se presenta un análisis retrospectivo de los resultados del tratamiento en 240 pacientes con neoplasias malignas del ovario. Se señala que el 36.6% de la serie global evolucionó de 1 a 5 años con 30 meses como promedio sin evidencia de actividad tumoral, cifra que incluye el 38% de las neoplasias epiteliales y el 30% de las de células germinales; el 65.5% de los estadios I, el 27.2% de los II (P<0.05 entre las etapas I y II), el 22.3% de las III y el 7.1% de los IV. El 23.5 de las enfermas tratadas únicamente con cirugía, el 42.7% de las manejadas con radioterapia postoperatoria (P<0.05 entre ambos grupos), y el 50% de las tratadas con quimioterapia. Se menciona que las pacientes en estadio I con mejor pronóstico, fueron aquellas tratadas con panhisterectomía y radioterapia externa al abdomen más sobredosis a la pelvis y que los mejores resultados en las etapas II y III, se obtuvieron con los siguientes 2 esquemas de tratamiento: panhisterectmía y omentectomía, seguida de radioterapia externa al abdomen más sobredosis a la pelvis y el mismo tratamiento quirúrgico, seguido de quimioterapia (55% y 60% de control de la enfermedad respectivamente)