Endometrial carcinoma: molecular alterations involved in tumor development and progression.

In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100,000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non-endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 10, PIK3CA, K-RAS and CTNNB1 (ß-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors.

Nuevas dianas terapéuticas en el melanoma / New Therapeutic Targets in Melanoma

La investigación sobre dianas moleculares en el melanoma sobre las que se pueda actuar farmacológicamente está empezando a dar sus primeros frutos. De todos los fármacos ensayados hasta el momento en pacientes con melanoma diseminado, los que han conseguido mejores resultados son los inhibidores de la mutación V600E de BRAF en los melanomas portadores de la misma, los inhibidores de la actividad tirosin-cinasa de c-Kit en melanomas con mutaciones de este gen y los anticuerpos anti-CTLA-4, inhibidores de los mecanismos de inmunotolerancia. Sin embargo, aún quedan muchos problemas por resolver, como la rápida adquisición de resistencias frente a los dos primeros tipos de fármacos o la falta de biomarcadores predictivos de respuesta frente al último de ellos. En este artículo presentamos una revisión sobre los resultados de los tratamientos contra estas y otras dianas en el melanoma diseminado y lo que parece que podemos esperar del futuro (AU)

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c-kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field (AU)

New therapeutic targets in melanoma.

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c-kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field.

The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms.

Sorafenib induces apoptosis and enhances Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced cell killing of tumoural cells. We have investigated the effects of the multikinase inhibitor Sorafenib alone or in combination with TRAIL and agonistic Fas antibodies on endometrial carcinoma cells. We have also focused on the search of the differential molecular mechanisms by which Sorafenib induces cell death and the ones involved in sensitisation to TRAIL. In the present study, we show that Sorafenib induces apoptosis of both endometrial cancer cell lines and human primary cultures and sensitises these cells to TRAIL and agonistic Fas antibodies (aFas)-induced apoptosis. However, Raf/MEK/ERK inhibition by Sorafenib was not responsible for Sorafenib cell death or TRAIL sensitisation of endometrial cancer cells. Sorafenib treatment correlated with a downregulation of both FLICE-Inhibitory Protein (FLIP) and myeloid cell leukaemia-1 (Mcl-1), caused by a proteasomal degradation of both proteins. We evaluated the contribution of FLIP and Mcl-1 downregulation in apoptosis triggered by Sorafenib alone or Sorafenib plus TRAIL. Interestingly, cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP. In contrast, we found that Sorafenib sensitisation of endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis was dependent on FLIP but not on Mcl-1 downregulation. Altogether, we discern the dual mechanisms by which Sorafenib causes cell death from those involved in death receptor sensitisation.

Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints.

This article reviews the main molecular alterations involved in endometrial carcinoma. Five molecular features (microsatellite instability, and mutations in the PTEN, k-RAS, PIK3CA and beta-catenin genes) are characteristic of endometrioid carcinomas, whereas non-endometrioid carcinomas show alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). The review also covers the phenomenon of apoptosis resistance, as well as the results obtained from cDNA array studies, and the perspectives for targeted therapies. A group of practical applications of molecular pathology techniques are also mentioned: diagnosis of hereditary non-polyposis colon cancer syndrome in patients with endometrial carcinoma; evaluation of precursor lesions; prognosis; diagnosis, particularly for synchronous endometrioid carcinomas of the uterus and the ovaries; and targeted therapies.

Expression of somatostatin receptors in human melanoma cell lines: effect of two different somatostatin analogues, octreotide and SOM230, on cell proliferation.

Somatostatin analogues (SAs) are potential anticancer agents. This study was designed to investigate the expression of somatostatin receptors (SSTRs) in melanoma cells and the effect of two SAs on cell proliferation and viability. Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and SOM230. Expression of SSTR1, SSTR2, SSTR3 and SSTR5 was assessed by real-time polymerase chain reaction. Proliferation, viability and cell death were assessed using standard assays. Inhibition was modelled by mixed-effect regression. Melanoma cells expressed one or more SSTR. Both SAs inhibited proliferation of most melanoma cell lines, but inhibition was < 50%. Neither SA affected cell viability or induced cell death. The results suggest that melanoma cell lines express SSTRs. The SAs investigated, under the conditions used in this study, did not, however, significantly inhibit melanoma growth or induce cell death. Novel SAs, combination therapy with SAs and their anti-angiogenic properties should be further investigated.

Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines.

BACKGROUND: Cutaneous malignant melanoma is an aggressive type of skin cancer which causes disproportionate mortality in young and middle-aged adults. Once disseminated, melanoma can be considered an incurable disease, highly resistant to standard antineoplastic treatment, such as chemotherapy or radiation therapy. The proteasome represents a novel target for cancer therapy that can potentially be used in melanoma. OBJECTIVES: To assess the effect of four structurally different proteasome inhibitors on human cutaneous melanoma-derived cell lines. METHODS: Sixteen human cutaneous melanoma-derived cell lines which are original were obtained from patients who were treated by two of the authors. Cells were cultured, exposed to proteasome inhibitors (bortezomib, ALLN, MG-132 and epoxomicin) and then assayed for cell cycle and cell death analyses. RESULTS: Proteasome inhibitors inhibited the in vitro growth of melanoma cells, and this effect was due to a reduction in cell proliferation rate and an induction of both caspase-dependent and caspase-independent cell death. Moreover, release of apoptosis-inducing factor was observed in the presence of the broad-specificity caspase inhibitor BAF (Boc-D-fmk). In addition, the four different proteasome inhibitors induced caspase 2 processing. CONCLUSIONS: This study provides information regarding the in vitro effects of proteasome inhibitors on melanoma cell lines, and the molecular mechanisms involved. It also gives support to the future use of such inhibitors in the treatment of patients with melanoma, either administered alone or in combination with other drugs.

CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising antineoplastic agent because of its ability to selectively kill tumoral cells. However, some cancer cells are resistant to TRAIL-induced apoptosis. We have previously demonstrated that in endometrial carcinoma cells such resistance is caused by elevated FLICE-inhibitory protein (FLIP) levels. The present study focuses on the mechanisms by which FLIP could be modulated to sensitize endometrial carcinoma cells to TRAIL-induced apoptosis. We find that inhibition of casein kinase (CK2) sensitizes endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis. CK2 inhibition correlates with a reduction of FLIP protein, suggesting that CK2 regulates resistance to TRAIL and Fas by controlling FLIP levels. FLIP downregulation correlates with a reduction of mRNA and is prevented by addition of the MG-132, suggesting that CK2 inhibition results in a proteasome-mediated degradation of FLIP. Consistently, forced expression of FLIP restores resistance to TRAIL and Fas. Moreover, knockdown of either FADD or caspase-8 abrogates apoptosis triggered by inhibition of CK2, indicating that CK2 sensitization requires formation of functional DISC. Finally, because of the possible role of both TRAIL and CK2 in cancer therapy, we demonstrate that CK2 inhibition sensitizes primary endometrial carcinoma explants to TRAIL apoptosis. In conclusion, we demonstrate that CK2 regulates endometrial carcinoma cell sensitivity to TRAIL and Fas by regulating FLIP levels.