Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

Inactivation of the E-Cadherin-Mediated Cell Adhesion System in Human Cancers

Abstract: It has long been known that cell-cell adhesiveness is generally reduced in human cancers. Tumor cells are dissociated throughout the entire tumor masses of diffuse-type cancers, whereas those of solid tumors with high metastatic potentials are often focally dissociated or dedifferentiated at the invading fronts. Thus, both irreversible and reversible mechanisms for inactivating the cell adhesion system appear to exist. This paper focuses on the cadherin system, which mediates Ca 2+ -dependent homophilic cell-cell adhesion. The E (epithelial)-cadherin-mediated cell adhesion system in cancer cells is inactivated by multiple mechanisms corresponding to the pathological features described above. Mutations have been found in the genes for E-cadherin and its undercoat proteins, α- and β-catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion. Transcriptional inactivation of E-cadherin expression was shown to occur frequently in tumor progression. E-cadherin expression in human cancer cells is regulated by CpG methylation around the promoter region. The cadherin system interacts directly with products of oncogenes, eg, c- erb B-2 protein and the epidermal growth factor receptor, and of the tumor suppressor gene, adenomatous polyposis coli (APC) protein, through β-catenin, which may be important in signal transduction pathways contributing to the determination of the biological properties of human cancers. In conclusion, inactivation of the E-cadherin system by multiple mechanisms, including both genetic and epigenetic events, plays a significant role in multistage carcinogenesis.

PIK3CA Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma

Abstract: Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate (PIP(3)) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP(3) homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.

MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators

Abstract: Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.

Oxidative Stress and Oxidative Damage in Carcinogenesis

Abstract: Carcinogenesis is a multistep process involving mutation and the subsequent selective clonal expansion of the mutated cell. Chemical and physical agents including those that induce reative oxygen species can induce and/or modulate this multistep process. Several modes of action by which carcinogens induce cancer have been identified, including through production of reactive oxygen species (ROS). Oxidative damage to cellular macromolecules can arise through overproduction of ROS and faulty antioxidant and/or DNA repair mechanisms. In addition, ROS can stimulate signal transduction pathways and lead to activation of key transcription factors such as Nrf2 and NF-kappaB. The resultant altered gene expression patterns evoked by ROS contribute to the carcinogenesis process. Recent evidence demonstrates an association between a number of single nucleotide polymorphisms (SNPs) in oxidative DNA repair genes and antioxidant genes with human cancer susceptibility. These aspects of ROS biology will be discussed in the context of their relationship to carcinogenesis.