Cancer stem cell: A rogue responsible for tumor development and metastasis.

Cancer stem cells are a small population of cells in a tumor. They have the ability to self-renew and maintain the tumor. The most apt and accepted hypothesis for tumor development is Cancer Stem Cells. This review focuses on this concept of cancer stem cells, serving their purpose and leading to the development of tumor. There are many cell biomarkers which have been described for the identification and characterization of cancer stem cells. The most prominent of the cellular markers for the detection of cancer stem cells; CD133, CD44, ALDH-1 along with some others have been discussed in detail in this review.

Genes and oral cancer.

Oral cancers have been one of the leading causes of deaths particularly in the developing countries. Prime reason for this high mortality and morbidity is attributed to the delay in diagnosis and prompt treatment. Relentless research in the field of oncology has led to the advent of novel procedures for the early detection of oral cancers. Molecular biology is highly promising in this regard. It is a procedure that detects alterations at a molecular level much before they are seen under a microscope and much before clinical changes occur. Molecular studies serve as the basis by which we will eventually be able not only to augment clinical assessment and classification of oral lesions but also predict malignant potential of oral lesions, thus reducing the incidence and increasing the scope for early diagnosis and treatment of oral cancers. However, making such sophisticated tools available for the common man in developing countries is one of the most important challenges faced today.

Analysis of p53, K-ras gene mutation & Helicobacter pylori infection in patients with gastric cancer & peptic ulcer disease at a tertiary care hospital in north India.

Background & objectives: Mutations in the oncogene and tumour suppressor genes play an important role in carcinogenesis. We investigated the association of p53 and K-ras gene mutation and Helicobacter pylori infection in patients with gastric cancer (GC) and peptic ulcer disease (PUD) attending a tertiary care hospital in north India. Methods: In total, 348 adult patients [62 GC, 45 PUD and 241 non-ulcer dyspepsia (NUD)] who underwent an upper gastrointestinal endoscopy were enrolled. H. pylori infection was diagnosed by rapid urease test, culture, histopathology and PCR. Mutation in the exon 5-8 of p53 gene was analyzed by PCR-single stranded conformational polymorphism (SSCP) and confirmed by sequence analysis. K-ras gene codon 12 mutation was analyzed by PCR-based restriction fragment length polymorphism. Results: Overall p53 gene mutation was found in 4.6 per cent of the study population, and its distribution in GC, PUD and NUD was 21, 4.4 and 0.4 per cent, respectively. p53 gene mutation was significantly higher in patients with GC than PUD (P<0.05) and NUD (P<0.001). No difference in p53 gene mutation was observed between H. pylori infected and non-infected individuals. K-ras gene mutation was absent in all the patients. Interpretation & conclusions: Our results show that p53 gene mutation may be associated with gastric carcinogenesis independent to H. pylori infection and absence of K-ras gene mutation questions its role in the pathogenesis of GC and PUD in Indian patients.

Patología molecular del cáncer pulmonar y sus lesiones precursoras: parte I, patología molecular del cáncer pulmonar / Molecular pathology of lung cancer and its precursor lesions: part I molecular pathology of lung cancer

En las últimas décadas se ha producido un gran avance en el conocimiento de las alteraciones moleculares que participan en la patogenia del cáncer pulmonar. Se ha determinado que esta neoplasia es el producto de un gran número de alteraciones genéticas (estimulando entre 10 y 20) que afectarían a oncogenes recesivos y a genes supresores de tumores. Además, se han establecido patrones de alteraciones genéticas en los diferentes tipos clínico-patológicos de cáncer pulmonar. Este conocimiento se ha aplicado al estudio de las alteraciones genéticas que participan en la progresión de las lesiones precursoras de esta neoplasia y al de sarrollo de métodos de detección precoz y control de pacientes con lesiones precursoras de cáncer pulmonar

Mutación del gen p53 en el cáncer de la vesícula biliar / P53 gene mutation in gallbladder cancer

Background: Gallbladder cancer frequency and mortality renders it one of the most important neoplastic diseases in Chile. P53 tumor suppressor gene has been studied in most types of cancer, but there is scarce information about it in gallbladder cancer. Aim: To study the frequency of P53 gene mutation in gallbladder cancer in the ninth region of Chile. Material and methods: In 25 pathological samples of gallbladder cancer, the direct amplification and sequencing of p53 gene exons 5,6,7,8-8 was possible. Results: Seventeen punctual mutations were observed in 13 cases (52 percent). There were 10 transitions, 5 transversions, one insertion (codon 194) and one deletion (codon 186). Eight cases had mutations in exon 5, six had mutations in exon 6, two had mutations in exon 7 and one had mutations in exons 8-9. In 14 of 25 cases, gene p53 protein was positive. When immunohistochemical expression of gene p53 protein was positive in more than 20 percent of cells, there was a high correlation between genetic alterations and immunohistochemical expression of the protein, with a specificity, sensitivity, positive and negative predictive values over 80 percent. Conclusions: P53 gene mutation is observed in a high proportion of gallbladder cancers at it can be accurately detected with conventional immunohistochemical techniques. The importance of this gene in the genesis of this carcinoma should be determined studying preneoplastic lesions and early carcinomas

Inactivación de genes supresores de tumores en la carcinogénesis del cuello uterino / Inactivation of tumor suppressor genes in uterine cervix carginogenesis

The importance of inactivation of tumor suppressor genes in the development/progression of carcinomas of the uterine cervix is reviewed. It is well known that HPV-related oncogenes are strongly linked to cervical cancer. However, fewer studies have explored the occurrence of inactivation of tumor suppressor genes in this neoplasia. Genetic deletions affecting tumor suppressor genes are the most common mechanism of inactivation of these genes. Studies using conventional molecular techniques such as restriction fragment length polymorphism (RFLP) and Southern Blot showed low frequency of deletions in cervical carcinomas. Detection of deletions by using RFLP and Southern Blot presents several disadvantages, the most important being the difficulty in analyzing pure tumor cells. More sensitive approaches include tissue microdissection and PCR analysis of microsatellites. Using these approaches, it has been shown that genetic deletions are, in fact, frequent events in cervical cancers, being detected in up to 95 percent of the cases. Multiple genetic loci are involved, including chromosomes 3p, 5p, 6p and 11q. Deletions are detected even in precursor lesions (cervical intraepithelial neoplasia, CIN). Some deletions have been correlated with prognostic parameters, such as stage, depth of invasion, and vascular space involvement. It is concluded that cervical carcinogenesis, like in other tumors, is a multistep process, characterized by the accumulation of events including activation of oncogenes, as well as inactivation of tumor suppressor genes

Virus y cáncer humano: genética molecular del cáncer cervicouterino / Virus and human carcinoma: molecular genetic and cervical carcinoma

El cáncer es un proceso multifactorial y con múltiples etapas. Los protooncogenes, antioncogenes y virus oncogénicos están involucrados en el desarrollo de diversas neoplasias. La expresión alterada de los protooncogenes (por mutaciones, rearreglos o amplificaciones), así como la cooperación entre ellos puede llevar a la célula a una estado transformado. Los genes p53 y RB codifican para dos proteínas antioncogénicas que regulan las decisiones celulares de proliferación o diferenciación. La ausencia de RB (pérdida de ambos alelos) lleva a la liberación de factores de transcripción. p53 en su forma mutada, favorece el crecimiento celular. El cáncer cervicouterino ejemplifica claramente la intervención de este tipo de factores en su desarrollo. Los papilomavirus humanos genitales (PVH) estan implicados en su etiología como iniciadores de la proliferación celular. La inactivación de las proteínas antioncogénicas p53 y p105 RB porparte de los oncogenes virales E6 y E7, respectivamente, mantiene el estado de divición celular continua. Adicionalmente, la participación de ooncogenes expresados en forma alterada (c-myc) y otros cofactores contribuyen a modificar los periodos de latencia y la gravedad de la enfermedad

Genetic alterations in head and neck squamous cell carcinomas

The genetic alterations observed in head and neck cancer are mainly due to oncogene activation (gain of function mutations) and tumor suppressor gene inactivation (loss of function mutations), leading to deregulation of cell proliferation and death. These genetic alterations include gene amplification and overexpression of oncogenes such as myc, erbB-2, EGFR and cyclinD1 and mutations, deletions and hypermethylation leading to p16 and TP53 tumor suppressor gene inactivation. In addition, loss of heterozygosity in several chromosomal regions is frequently observed, suggesting that other tumor suppressor genes not yet identified could be involved in the tumorigenic process of head and neck cancers. The exact temporal sequence of the genetic alterations during head and neck squamous cell carcinoma (HNSCC) development and progression has not yet been defined and their diagnostic or prognostic significance is controversial. Advances in the understanding of the molecular basis of head and neck cancer should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease

TGF-beta1 inhibition of apoptosis through the transcriptional up-regulation of Bcl-X(L) in human monocytic leukemia U937 cells

To characterize the TGF-beta1 response of monocytic leukemia cells, we analyzed the effects of TGF-beta1 on cell proliferation, differentiation, and apoptosis of human monoblastic U937 cells. Treatment of cells with TGF-beta1 in the absence of growth factors significantly enhanced cell viability. Flow cytometric analysis of DNA content and CD14 expression revealed that TGF-beta1 does not affect cell proliferation and differentiation. Consistent with these results was the finding that no transcriptional induction of Cdk inhibitors such as p21Waf1, p15Ink4b, and p27Kip1 was detected following TGF-beta1 treatment. Interestingly, however, pretreatment of TGF-beta1 significantly inhibited Fas-, DNA damage-, and growth factor deprivation-induced apoptosis. This antiapoptotic effect was totally abrogated by anti-TGF-beta1 antibody. Quantitative RT-PCR analysis demonstrated a dose- and time-dependent transcriptional up-regulation of Bcl-X(L), suggesting its implication in the TGF-1-mediated antiapoptotic pathway. We also observed elevated expression of c-Fos and PTEN/MMAC1. But, no detectable change was recognized in expression of c-Jun, Fas, Fadd, Fap-1, Bcl-2, and Bax. Taken together, our study shows that TGF-beta1 enhancement of cellular viability is associated with its antiapoptotic effect, which may result from the transcriptional up-regulation of Bcl-X(L).

Cell cycle control and cancer.

This review consists of two parts. In the first part normal mechanisms regulating the progression of cells through the cell cycle are briefly reviewed. Besides mitogenic stimulation, cyclin kinase inhibition, the G1 restriction point and the prb pathway, accuracy of DNA replication and DNA repair, the G2 to M transition, apoptosis and the p 53 pathway, proteolytic, in particular ubiquitin-dependent mechanisms involved in the initiation of DNA synthesis in the separation of sister chromatids and in the telophase to GO/G1 transition, are discussed. In the second part oncogene and tumor suppressor gene products are briefly characterized. Aberrations of cell cycle control mechanisms associated with cancer are grouped as follows: deregulation of protooncogenes by translocations juxtaposing protooncogenes to immunoglobulin--or T cell receptor genes; translocations producing chimeric proteins unique to cancer cells; inversions and amplifications resulting in over expression of regulator genes; and deletions and mutations of tumor suppressor genes. It is emphasized that cancer is the result of a multistep process and that uncontrolled cell production and other alterations are, as a rule, late phenomena.

A genética molecular de sarcomas de partes moles e sua aplicação à clínica / The molecular genetics of soft tissue sarcomas and its clinical application

Sarcomas de partes moles, como outros tumores humanos, são causados por mutações em genes supressores de tumores e oncogenes. Entre eles alguns, como p53 por exemplo, são freqüentemente detectados na forma mutatada em sarcomas e outros tumores humanos. De outro lado, há várias mutações altamente específicas para determinados sarcomas que podem servir como marcadores diagnósticos de alto valor. Exemplos de mutações de potencial diagnóstico incluem a translocação entre PAX3 e FKHR em rabdomiossarcoma alveolar, a translocação entre EWS e FLI-1 em tumores neuroectodérmicos periféricos primitivos e EWS e ATF-1 e sarcomas de células claras. Todas essas translocações podem ser detectadas por metodologias moleculares e que podem constituir um componente importante de repertório diagnóstico futuro.

Cáncer cérvico-uterino. Influencia de los genes celulares y de los virales: implicaciones en el desarrollo de vacunas / Cervico-uterine Cancer. The influence of cellular and viral genes: implications in vaccine development

El cáncer humano constituye un importante problema de salud; en particular, el cáncer cérvico-uterino es frecuente en países latinoamericanos. Los oncogenes activados (myc y ras, por ejemplo) y los antioncogenes (p53 o Rb), al inactivarse participan en los múltiples pasos de la carinogénesis. Además, algunos virus están asociados con el cáncer humano. Por ejemplo, los papilomavirus humano (PVH) de alto riesgo están involucrados en carcinoma cérvico-uterino. La tipificación del PVH es importante para el diagnóstico y el pronóstico de esta enfermedad. El entendimiento de la bioquímica y de la genética molecular de los genes supresores de tumor, de los congenes celulares y de los virus tumorigénicos, abre nuevas posibilidades en el diagnóstico, la vacunación, así como en la terapia del cáncer cérvicouterino

Genética molecular do câncer: implicaçöes no câncer de tiróide / Molecular genetics of cancer: insights into human thyroid neoplasm

Recentes avanços em genética molecular têm permitido a compreensäo de uma série de mecanismos envolvidos no aparecimento e desenvolvimento de tumores. Revemos conceitos básicos sobre o ciclo celular e os mecanismos fisiológicos de controle da divisäo celular. Descrevemos a visäo atual do papel dos oncogenes e genes supressores tumorais na etiopatogenia do câncer, enfatizando novos conceitos sobre instabilidade genômica. Revemos alguns dos principais oncogenes e genes supressores tumorais e seu papel no câncer de tiróide. Aplicaçöes da genética molecular no diagnóstico e terapêutica do câncer säo lembradas salientando futuras perspectivas.

O envolvimento de genes e proteínas na regulaçäo da apoptose - carcinogênese / The involvement of genes and proteins in apoptosis - carcinogenesis regulation

A apoptose é um fator importante em muitos processos biológicos normais, tais como a embriogênese, o desenvolvimento do sistema imune, a maturaçäo e a diferenciaçäo celular. Em situaçöes patológicas, a apoptose parece estar implicada na imunodeficiência, resistência a drogas e carcinogênese. Sabe-se que a carcinogênese envolve alteraçöes genéticas cumulativas em oncogenes e genes supressores de tumor. Dessa forma, o prognóstico de cada tumor humano parece depender do equilíbrio entre os diversos genes, sendo previsível que um conhecimento mais profundo da cooperaçäo e antagonismo entre esses genes possa fornecer num futuro próximo informaçöes clinicamente relevantes. Nós revisamos alguns dos mais recentes progressos a respeito de genes envolvidos na apoptose e nos cânceres humanos (p53, bcl-2, c-myc, fas-APO-1, mdr-1) e suas implicaçöes clínicas.

Genética y cáncer / Genetics and cancer

Cuando se observa la evolución que ha tenido la historia de la medicina a través de los siglos se puede apreciar que hay una serie de etapas que marcan su progresivo desarrollo. Entre las múltiples etapas que se observan hay que destacar 3 grandes hitos, que han tenido una trascendencia fundamental en el arte de prevenir y curar las enfermedades