Cancer chemotherapy failure: a synthetic view

Cancer is a highly prevalent and fatal disease, being one of the main causes of death in Brazil and in the world. In the last decades, a great advance has been reached in fight against cancer, with some translation in curability. However, these advances are still insufficient, and the prognosis of the cancer patient is usually unfavorable. Indeed, there are still many gaps in our knowledge about this complex and heterogeneous disease. Several treatments approaches against cancer are available to clinical practice - and some others are being developed - one of which is chemotherapy, both traditional and targeted therapy (TT), used - above all - as primary treatment for metastatic or secondary treatment in local or locally advanced disease. Several factors can act through many mechanisms to determine the failure of chemotherapy treatment. These factors are distributed across the various biological scales, from the molecular to the socioeconomic level, making the holistic view of treatment a great challenge and impairing the awareness of what can go wrong. The purpose of this paper is to be a comprehensive - but not superficial - picture of the many factors that influence the success of chemotherapy. In this way, the result of this work was this discussion on chemotherapy failure, were it was exposed recent advances, challenges to be overcome and new paths to be explored on this field.O Câncer é uma doença de alta prevalência e letalidade, sendo uma das principais causas de morte no Brasil e no mundo. Nas últimas décadas, grandes avanços foram alcançados na luta contra o câncer, com alguma tradução em curabilidade. Contudo, esses avanços ainda não são suficientes, de modo que o prognóstico do paciente com câncer ainda é, geralmente, desfavorável. De fato, há ainda diversas lacunas em nosso conhecimento a respeito dessa complexa e heterogênea doença. Diversos tratamentos contra o câncer já estão disponíveis à prática clínica - e outros ainda estão sendo desenvolvidos - uma delas a quimioterapia, tanto a tradicional quando a alvo dirigida, utilizada, sobretudo, como tratamento primário contra doença metastática ou secundário contra doença local ou localmente avançada. Diversos fatores podem atuar, através de vários mecanismos, de modo a determinar a falha do tratamento quimioterápico. Esses fatores estão distribuídos ao longo de diversas escalas biológicas, do nível molecular ao socioeconômico, tornando uma visão holística do tratamento um grande desafio, prejudicando a compreensão acerca do que pode dar errado. O objetivo deste trabalho é ser uma leitura compreensiva - mas não superficial - dos muitos fatores que influenciam o sucesso de quimioterapia. Deste modo, o resultado foi a presente discussão, na qual foram expostos avanços recentes, desafios a serem superados e novos caminhos a serem explorados na área

Galectin-3 and beta-catenin expression in premalignant and carcinomatous lesions in tongue of mice

INTRODUÇÃO: A galectina-3 (GAL3) apresenta importantes papéis na biologia tumoral e recentemente foi mostrada a sua participação na via de sinalização Wnt, translocando a beta-catenina para o núcleo. Expressão alterada de GAL3 e beta-catenina tem sido descrita em cânceres, mas não há estudos avaliando a expressão de ambas em displasias e carcinomas desenvolvidos em modelos de carcinogênese de língua. OBJETIVOS: Estudar a expressão de GAL3 e beta-catenina em lesões displásicas e carcinomas induzidos experimentalmente em língua de camundongos. MATERIAL E MÉTODOS: Vinte camundongos C57BL/6 machos foram desafiados com 4NQO na água de beber por 16 semanas e sacrificados na semana 16 e 32. Após o sacrifício, as línguas foram removidas, processadas, coradas por hematoxilina e eosina (HE) para detecção de displasias e carcinomas. Ensaio imuno-histoquímico foi realizado para determinar o índice de positividade para GAL3 e beta-catenina nessas lesões, bem como uma correlação entre elas em carcinomas. RESULTADOS: O número de camundongos afetados por carcinoma aumentou entre as semanas 16 e 32 (22,2% vs. 88,9%) e o de displasia diminuiu (66,7% vs. 11,1%). Um aumento de células positivas para beta-catenina não membranosa e GAL3 citoplasmática foi observado nas displasias e nos carcinomas, mas essa diferença não foi estatisticamente significativa. No entanto, um aumento estatisticamente significativo de GAL3 nuclear foi observado na evolução de displasia para carcinoma (p = 0,04). Nenhuma correlação foi encontrada entre beta-catenina e GAL3. CONCLUSÃO: Tanto nas displasias quanto nos carcinomas a via de sinalização Wnt está ativa, e o aumento de GAL3 nuclear nos carcinomas sugere um papel na transformação maligna do epitélio lingual.INTRODUCTION: Galectin-3 plays pivotal role in tumor biology and its participation in Wnt signaling pathway translocating beta-catenin into the nucleus has been recently demonstrated. Altered galectin-3 and beta-catenin expressions have been described in different tumors, however, there are no studies evaluating their expression in dysplasias and carcinomas induced in carcinogenic tongue models. OBJECTIVES: To study galectin-3 and beta-catenin expressions in dysplasias and carcinomas experimentally induced in mouse tongue. METHODS: Twenty C57Bl/6 male mice were treated with 4NQO in their drinking water for 16 weeks and sacrificed at weeks 16 and 32. Tongues were removed, routinely processed, and stained with hematoxylin and eosin to detect dysplasias and carcinomas. An immunohistochemical assay was performed to determine the level of positivity for galectin-3 and beta-catenin in these lesions as well as their correlation in carcinomas. RESULTS: The number of mice affected by carcinomas increased from week 16 to week 32 (22.2% vs. 88.9%) and the number affected by dysplasias decreased (66.7% vs. 11.1%). There was an increase in non-membranous beta-catenin- and cytoplasmic galectin-3-positive cells in dysplasias and carcinomas, although this difference was not statiscally significant. Nonetheless, there was a significant increase of nuclear galectin-3-positive cells in the evolution from dysplasia to carcinoma (p = 0.04). There was no correlation between beta-catenin and galectin-3. CONCLUSION: Wnt signaling pathway is active in both dysplasias and carcinomas and the increase of nuclear galectin-3-positive cells in carcinomas suggests its influence on malignant transformation in the tongue epithelium.(FAPEMIG) Fundação de Amparo à Pesquisa do Estado de Minas Gerai

Tumors as complex organs: are cancers manageable through the modification of their microenvironment?

FAPESP (Center for Cell-based Therapy Research), Instituto Nacional de Ciência e Tecnologia- Redoxoma and UICC-Yamagiwa Yoshida Grant

Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis:a Systematic Analysis

Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy

An Antibody to De-N-Acetyl Sialic Acid Containing-Polysialic Acid Identifies an Intracellular Antigen and Induces Apoptosis in Human Cancer Cell Lines

Polysialic acid (PSA), an α2,8-linked homopolymer of N-acetylneuraminic acid (Neu5Ac), is developmentally regulated and its expression is thought to be restricted to a few tissues in adults. Recently, we showed that two human pathogens expressed a derivative of PSA containing de-N-acetyl sialic acid residues (NeuPSA). Here we show that an epitope identified by the anti-NeuPSA monoclonal antibody, SEAM 3 (SEAM 3-reactive antigen or S3RA), is expressed in human melanomas, and also intracellularly in a human melanoma cell line (SK-MEL-28), a human T cell leukemia cell line (Jurkat), and two neuroblastoma cell lines (CHP-134 and SH-SY5Y). SEAM 3 binding induced apoptosis in the four cell lines tested. The unusual intracellular distribution of S3RA was similar to that described for the PSA polysialyltransferases, STX and PST, which are also expressed in the four cell lines used here. Interestingly, suppression of PST mRNA expression by transfection of SK-MEL-28 cells with PST-specific short interfering RNA (siRNA) resulted in decreased SEAM 3 binding. The results suggest further studies of the utility of antibodies such as SEAM 3 as therapeutic agents for certain malignancies

Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications

Background: the process of gastric carcinogenesis still remains to be elucidated. the identification of genes related to this process may help to reduce mortality rates through early diagnosis and the development of new anticancer therapies. Nucleophosmin 1 (NPM1) acts in ribosome biogenesis, centrosome duplication, maintenance of genomic stability, and embryonic development. Recently, NPM1 has been implicated in the tumorigenesis processes. Here, we evaluated NPM1 gene and protein expression in gastric tumors and in corresponding non-neoplastic gastric samples.Methods: NPM1 protein expression was determined by Western blot in 17 pairs of gastric tumors and corresponding non-neoplastic gastric tissue. the protein immunoreactivity was observed in 12 tumor samples. mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in 22 pairs of gastric tumors and in matched non-neoplastic gastric tissue.Results: NPM1 protein expression was significantly reduced in gastric cancer samples compared to matched non-neoplastic gastric samples (P = 0.019). the protein level of NPM1 was reduced at least 1.5-fold in 35% of tumors compared to paired non-neoplastic gastric tissue. However, NPM1 immunoreactivity was detected in neoplastic and non-neoplastic cells, including in intestinal metaplastic, gastritis and inflammatory cells. NPM1 was mainly expressed in nucleus and nucleolus subcellular compartments. the staining intensity and the percentage of immunoreactive cells varied among the studied cases. the NPM1 mRNA level was reduced at least 1.5-fold in 45.5% of samples and increased in 27.3% of samples. An inverse correlation between protein and mRNA expression was detected (r = -0.509, P = 0.037). Intestinal-type gastric cancer presented higher mRNA levels than diffuse-type (P = 0.026). However, reduced NPM1 protein expression was associated with intestinal-type gastric cancer compared to matched non-neoplastic gastric samples (P = 0.018). in addition, tumors from patients with known distant metastasis presented reduced NPM1 protein levels compared to tumors from patients without distant metastasis (P < 0.001).Conclusion: Although the expression of NPM1 is heterogeneous in gastric tumors, our results suggest that NPM1 down-regulation may have a role in gastric carcinogenesis and may help in the selection of anticancer treatment strategies.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped & Traumatol, BR-04038031 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Radiol, Expt Oncol Lab, BR-01246903 São Paulo, BrazilSão Paulo State Canc Inst, Ctr Translat Oncol, BR-01246000 São Paulo, BrazilFed Univ Para, Joao de Barros Barreto Univ Hosp, Oncol Res Ctr, BR-60673000 Belem, Para, BrazilFed Univ Para, Inst Biol Sci, Human Cytogenet Lab, BR-66073000 Belem, Para, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped & Traumatol, BR-04038031 São Paulo, BrazilWeb of Scienc

A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production

In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Uniao Quimica Farmaceutica NacionalConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Inst Butantan, Lab Bioquim & Biofis, BR-05503900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilInst Butantan, Programa Posgrad Interunidades Biotecnol, USP, IPT, BR-05503900 São Paulo, BrazilUniv São Paulo, Fac Med, Lab Oncol Expt LIM24, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilFAPESP: FAPESP 2010/52669-3FAPESP: CAT/CEPID - 1998/14307-9Web of Scienc