Cancer is the natural end-state of multicellular organisms Any population of organisms that shows hereditary variation in reproductive capacity will evolve by natural selection. Genotypes that reproduce faster or more extensively will come to dominate later generations, only to be supplanted in turn by yet more efficient reproducers. Exactly the same applies to the population of cells that constitutes a multicellular organism like man. Cellular proliferation is under genetic control, and if somatic mutation creates a variant that proliferates faster, the mutant clone will tend to take over the organism. Thus people have a natural tendency to turn into tumors.

No single mutation can escape these mechanisms and convert a normal cell into a malignant one. Long ago, studies of the age-dependence of cancer suggested that on average 6–7 successive mutations are needed to convert a normal cell into an invasive carcinoma. In other words, only if half a dozen independent defenses are disabled by mutation can a normal cell convert into a malignant tumor.

Genes afetados em células cancerosas Oncogenes: Oncogenes (Sections 18.3 and 18.4). These are genes whose normal activity promotes cell proliferation. Gain of function mutations in tumor cells create forms that are excessively or inappropriately active. A single mutant allele may affect the phenotype of the cell. The non-mutant versions are properly called proto-oncogenes. Tumor suppressor (TS) genes (Section 18.5). TS gene products inhibit events leading towards cancer. Mutant versions in cancer cells have lost their function. Some TS gene products prevent cell cycle progression, some steer deviant cells into apoptosis, and others keep the genome stable and mutation rates low by ensuring accurate replication, repair and segregation of the cell's DNA. Both alleles of a TS gene must be inactivated to change the behavior of the cell.

A multiplicação celular é controlada G1 (START/restriction point): o DNA deve ser replicado ? G2 : controle qualidade: o DNA replicado está em boas condições? M: os cromossomos estão corretamente alinhados? n recent years, the way in which cell division is controlled has been clarified. Inside each cell there is a cell cycle ‘clock’ which determines whether or not a cell should divide. The clock is an executive decision maker and integrates the regulatory signals received by the cell with the current state of health of the cell. The cell cycle consists of four steps. In the gap 1 (G1) phase, the cell grows in size and checks the status of its internal systems. If everything is functioning normally, and any damage to the DNA has been corrected, the cell moves on through the cycle. If something is wrong and cannot be corrected, the cell halts its progression through the cycle and may initiate apoptosis and close down. R marks the point where restriction of the cycle can occur. In the following synthetic (S) phase, the cell replicates its store of DNA in the chromosomes. Following this there is a period of preparation for division called the G2 phase. Then the cell divides - the mitotic (M) phase. The two new daughter cells then enter the G1 phase of their own cell cycle. This sequence of events involves interactions between many different proteins, some of which are capable of halting the process if conditions are unfavourable. p53 is a tumour suppressor protein that binds to specific DNA sequences. It is thought of as the "guardian of the genome" and controls the cell cycle to enable the repair of damaged DNA. The control of cell proliferation is intimately connected to apoptosis - a process by which cells methodically close down their metabolic activities and die when they have irreparable damage to their DNA or have no further role in the body. Normal p53 suppresses tumour growth by arresting cells in G1 phase or triggering apoptosis. The p53 gene is mutated in a wide range of tumours, for example: skin cancer and colorectal cancer, with the result that in the affected cells the cell cycle clock spins out of control and the cells divide without restraint. Gene p53 Apoptose (morte celular)

Controle do ciclo celular

Controle do ciclo celular Ciclinas G2 (A e então B): atuam sobre proteínas que regulam a divisão da célula, tais como aquelas que controlam condensação do DNA, quebra do envelope nuclear e montagem do aparato mitótico Ciclinas G1 (ciclina D e então E): atuam sobre proteínas que regulam a iniciação da replicação do DNA Ciclinas S (E e então A): atuam sobre proteínas envolvidas na regulação da replicação do DNA A concentração de cinase dependente de ciclina é constante !

Controle da expressão gênica Figure 17-30. Mechanisms controlling S-phase initiation in animal cells. G1-Cdk activity (cyclin D-Cdk4) initiates Rb phosphorylation. This inactivates Rb, freeing E2F to activate the transcription of S-phase genes, including the genes for a G1/S-cyclin (cyclin E) and S-cyclin (cyclin A). The resulting appearance of G1/S-Cdk and S-Cdk activities further enhances Rb phosphorylation, forming a positive feedback loop. E2F acts back to stimulate the transcription of its own gene, forming another positive feedback loop.

A multiplicação celular é controlada Apoptose n recent years, the way in which cell division is controlled has been clarified. Inside each cell there is a cell cycle ‘clock’ which determines whether or not a cell should divide. The clock is an executive decision maker and integrates the regulatory signals received by the cell with the current state of health of the cell. The cell cycle consists of four steps. In the gap 1 (G1) phase, the cell grows in size and checks the status of its internal systems. If everything is functioning normally, and any damage to the DNA has been corrected, the cell moves on through the cycle. If something is wrong and cannot be corrected, the cell halts its progression through the cycle and may initiate apoptosis and close down. R marks the point where restriction of the cycle can occur. In the following synthetic (S) phase, the cell replicates its store of DNA in the chromosomes. Following this there is a period of preparation for division called the G2 phase. Then the cell divides - the mitotic (M) phase. The two new daughter cells then enter the G1 phase of their own cell cycle. This sequence of events involves interactions between many different proteins, some of which are capable of halting the process if conditions are unfavourable. p53 is a tumour suppressor protein that binds to specific DNA sequences. It is thought of as the "guardian of the genome" and controls the cell cycle to enable the repair of damaged DNA. The control of cell proliferation is intimately connected to apoptosis - a process by which cells methodically close down their metabolic activities and die when they have irreparable damage to their DNA or have no further role in the body. Normal p53 suppresses tumour growth by arresting cells in G1 phase or triggering apoptosis. The p53 gene is mutated in a wide range of tumours, for example: skin cancer and colorectal cancer, with the result that in the affected cells the cell cycle clock spins out of control and the cells divide without restraint. Prêmio Nobel em Fisiologia ou Medicina (2001) Leland H. Hartwell, R. Timothy (Tim) Hunt and Paul M. Nurse

Tumor e câncer Tumor (neoplasma): conjunto de células que se multiplicam sem controle Tumor benigno: células neoplásicas permancem unidas (podem ser removidas cirugicamente) Tumor maligno (câncer): células podem colonizar outros tecidos Células cancerosas: Não têm regulação do crescimento São imortais (crescem ativamente sempre) Invadem outros tecidos

Câncer

Câncer

Genética do câncer Alteram o controle do ciclo celular Alteram a morte celular

Mutações em genes que controlam o ciclo celular Table 18.1. Human and animal tumor viruses Mutações em genes que controlam o ciclo celular Oncogenes: Mutações que causam hiperatividade levam a divisões sem interrupção Mutação é dominante. Proto-oncogene: é a forma não mutada, normal, que estimula a divisão, mas não é hiperativa. Gene supressor de tumor: - inibe a divisão celular - leva à apoptose (morte celular) - mantém taxas de mutação baixas Mutações podem causar divisões celulares “sem freio” - mutação é recessiva

Controle da expressão gênica Câncer da mama: genes que codificam D1-Cdk4 estão amplificados Figure 17-30. Mechanisms controlling S-phase initiation in animal cells. G1-Cdk activity (cyclin D-Cdk4) initiates Rb phosphorylation. This inactivates Rb, freeing E2F to activate the transcription of S-phase genes, including the genes for a G1/S-cyclin (cyclin E) and S-cyclin (cyclin A). The resulting appearance of G1/S-Cdk and S-Cdk activities further enhances Rb phosphorylation, forming a positive feedback loop. E2F acts back to stimulate the transcription of its own gene, forming another positive feedback loop.

Alteração na apoptose causa câncer G1 (START/restriction point): o DNA deve ser replicado ? G2 : controle qualidade: o DNA replicado está em boas condições? M: os cromossomos estão corretamente alinhados? Apoptose (morte celular) Proteína Bcl-2 bloqueia apoptose. Em linfomas (câncer das células do sangue) o gene é translocado para outro cromossomo, próximo a um promotor muito ativo.

p53: gene supressor de tumor Gene mutado em metade dos tipos de câncer humanos. Proteína p53: ativada por dano no DNA Bloqueia progressão para fase S pela indução da expressão do gene p21. Proteína p21 bloqueia ação do complexo cdk/ciclina necessária para passagem para fase S Estimula a apoptose Em câncer de pele e colorretal está mutado n recent years, the way in which cell division is controlled has been clarified. Inside each cell there is a cell cycle ‘clock’ which determines whether or not a cell should divide. The clock is an executive decision maker and integrates the regulatory signals received by the cell with the current state of health of the cell. The cell cycle consists of four steps. In the gap 1 (G1) phase, the cell grows in size and checks the status of its internal systems. If everything is functioning normally, and any damage to the DNA has been corrected, the cell moves on through the cycle. If something is wrong and cannot be corrected, the cell halts its progression through the cycle and may initiate apoptosis and close down. R marks the point where restriction of the cycle can occur. In the following synthetic (S) phase, the cell replicates its store of DNA in the chromosomes. Following this there is a period of preparation for division called the G2 phase. Then the cell divides - the mitotic (M) phase. The two new daughter cells then enter the G1 phase of their own cell cycle. This sequence of events involves interactions between many different proteins, some of which are capable of halting the process if conditions are unfavourable. p53 is a tumour suppressor protein that binds to specific DNA sequences. It is thought of as the "guardian of the genome" and controls the cell cycle to enable the repair of damaged DNA. The control of cell proliferation is intimately connected to apoptosis - a process by which cells methodically close down their metabolic activities and die when they have irreparable damage to their DNA or have no further role in the body. Normal p53 suppresses tumour growth by arresting cells in G1 phase or triggering apoptosis. Apoptose (morte celular)

Conseqüências da progressão com danos no DNA

Hipótese de “two hits” para formação de tumor Retinoblastoma (1971, Knudson)

Vírus podem induzir tumores

Papiloma Proteínas E7 e E6 do vírus inativam as proteínas Rb e p53

Human adenovirus Human papillomavirus SV40 Diversos vírus que causam tumores codificam proteínas que se ligam e inativam a proteína Rb Human papillomavirus SV40

Oncogenes e supressores de tumor Supressor de tumor

Conversão de proto-oncogene em oncogene

Alterações genéticas e oncogenes Superprodução de proteínas do proto-oncogene  oncogene Proto-oncogene atividade normal  oncogene (hiperatividade)

Câncer de cólon Pólipo adenomatoso Carcinoma

Evolução do câncer: vários estágios Mutações para aumentar a proliferação celular, aumentando os “alvos” para novas mutações Mutaçõs que afetam a estabilidade do genoma como um todo, aumentando a taxa de mutação. Mutações que afetam diversas atividades celulares

Progressão do câncer de cólon

Câncer no mundo

Probabilidade de desenvolver câncer em alguma fase da vida (EUA 1997-1999) Risco Todos lugares 1 in 2 Próstata 1 in 6 Pulmão e brônquios 1 in 13 Colo e reto 1 in 17 Bexiga urinária 1 in 29 Linfoma Non-Hodgkin 1 in 47 Melanoma 1 in 57 Leucemia 1 in 69 Cavidade oral 1 in 71 Rim 1 in 72 Estômago 1 in 79 Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and Population Sciences, National Cancer Institute, 2002.

Cigarro e câncer de pulmão Morte por câncer de pulmão em homens Consumo per capita de cigarro Morte em mulheres *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

Telômeros e câncer