RESUMO
Gastric cancer is a leading cause of death worldwide. Nowadays, complete surgical resection and TNM at diagnosis are the main prognostic factors. In spite of this, many patients will have a recurrence after surgery and die within a few months or years. That means that we need more accurate prognostic factors to design specific approaches for individual patients. Chromosome instability is a feature of gastric cancer commonly associated to chromosomal aberrations that leads to major modifications of DNA content globally termed as aneuploidy. In this regard, many authors' opinions diverge regarding the clinical impact of aneuploidy. This review will summarise data on the clinical impact of aneuploidy on clinical practice, the biological mechanisms that underlie chromosomal instability that induces aneuploidy and the relevance of specific chromosomal aneuploidy to cancer biology.
Assuntos
Aneuploidia , Neoplasias Gástricas/genética , Animais , Centrossomo/metabolismo , Humanos , Fuso Acromático , Neoplasias Gástricas/patologiaRESUMO
DNA repair pathways enable tumour cells to survive DNA damage induced by external agents such as therapeutic treatments. Signalling cascades involved in these pathways comprise the DNA-dependent protein kinase (DNA-PK), Ataxia-telangiectasia mutated (ATM), ATM and Rad3 related (ATR) and checkpoint kinases I and 2 (Chk1/Chk2), among others. ATM and ATR phosphorylate, respectively, Chk2 and Chk1, leading to activation of checkpoints. Chk2 acts as a signal distributor, dispersing checkpoint signal to downstream targets such as p53, Cdc25A, Cdc25C, BRCA1 and E2F1. A role of Chk2 as a candidate tumour suppressor has been suggested based on both mouse genetics and somatic tumour studies. We will discuss here the possible role of this kinase in human carcinogenesis and the possibility to use it as a target to increment DNA damage in cancer cells in response to DNA-damaging therapies.
Assuntos
Neoplasias/enzimologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Quinase do Ponto de Checagem 2 , Dano ao DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidoresRESUMO
The nuclear factor kappa B (NFkappaB) signalling pathway regulates the expression of hundreds of genes that are involved in different cellular processes such as cell proliferation, survival, stress responses, cellular immunity and inflammation. Its aberrant regulation is involved in several pathologies, but its relevance in cellular transformation and cancer development has been extensively studied. Mutations in the core components of NFkappaB as well as in the cellular machinery that regulates its activation have been found in many types of tumours. On the other hand, its role in promoting cell survival is an important obstacle in many cancer therapies. The development of chemical inhibitors that block NFkappaB activation acting either directly on IKKs or on the proteosome machinery has shown antitumour and proapoptotic activity both in preclinical and clinical studies.
Assuntos
NF-kappa B/fisiologia , Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Humanos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Chemotherapy and radiation are two important modalities for cancer treatment. Many agents in clinical used have the ability to induce DNA damage, however they may be highly cytotoxic as a secondary effect. Different mechanisms are involved both, in detection and repair of DNA damage. The modulation of these pathways, has a great impact on clinical outcome and is frequently responsible of therapeutic resistance. Therefore, pharmacological inhibition of DNA damage repair pathways has been explored as a useful strategy to enhance chemo and radiosensitivity, thus it could be used for reversing drug resistance. Different agents have shown excellent results in preclinical studies in combination with radiation or chemotherapy. Early phase clinical trials are now being carried out using different DNA repair inhibitors targeting several enzymes such as PARP, DNA-PK or MGMT.