Cancer

Cancer

Vipin Shankar

Cancer; the current scenario 

Causes about one fifth of deaths in the world.

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Between 100 and 350 of every 100,000 deaths is caused by cancer.

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Cancer occurs due to failure of the mechanisms that control the growth and proliferation of cells.

Cancer: facts 

During normal development and throughout adult life, intricate genetic control systems regulate the balance between cell birth and death in response to growth signals, growthinhibiting signals, and death signals.

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Cell birth and death rates determine adult body size, and the rate of growth in reaching that size.

Cancer: Incidence 

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The incidence of cancer increases exponentially with age in a human population from the age of ~40 to -80 This suggests that cancer is the result of the occurrence of a series of independent events. From the trend of the curve we can estimate that a range of 4-10 stochastic events are required to generate a cancer.

Types of cancer 

Cancer can result from abnormal proliferation of any of the different kinds of cells in the body, so there are more than 100 distinct types of cancer. 

Tumor : any abnormal proliferation of cells, which may be either benign or malignant.

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Benign tumor : remains confined to original location, neither invading surrounding cells nor spreading to distant bodies.

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Malignant tumor : capable of both invading surrounding tissue and spreading throughout the body via the circulatory or lymphatic system (metastasis).

Types of cancer… 

Both benign and malignant tumors are classified according to the type of cell from which they arise. 

Carcinoma : malignancies of the epithelial cells.

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Sarcoma : solid tumors of the connective tissue such as muscle, bone and cartilage.

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Leukemia and Lymphoma : arise from blood forming cells and from cells of the immune system.

Cancer development 

The development of cancer can be studied under 

Tumor initiation : results from a genetic alteration leading to abnormal proliferation of a single cell.

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Tumor progression : continues as additional mutations occur within the cells of the tumor population.

Cancer development… 

The basic model for the occurrence of cancer is that cancer is a multistage process in which initiation of a tumor requires several steps, which may then be followed by further changes to strengthen the tumorigenic state.

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Tumor progression is then driven by selection among the tumor cells for those that can grow more aggressively.

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The two major types of change in the genome are the accumulation of somatic mutations and the development of genetic instability.

Cancer development… 

Most cancer cells have an increased number of mutations compared to normal cells.

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As the cancer progresses, the number of mutations increases.

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The occurrence of different mutations creates an opportunity to select among the population for cells with particular properties.

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In the case of cancer, a mutation that increases the growth potential of a cell will give it a selective advantage.

Cancer development… 

At each stage during the progression of a cancer, the cell population is selected for those cells that can grow more aggressively (this meaning initially that they can grow more rapidly and later that they can migrate to start colonies in new locations).

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Our current view of cancer is that it is driven by twin features: an increased rate of mutation is responsible for generating cells with altered growth properties; and the population of cells is then selected for those with an increased rate of proliferation.

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A cancer progresses by multiple cycles of mutation and selection.

Cancer development… 

By comparing cancer cells with normal cells, we can identify genes that have been changed by mutation.

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Those that have direct effects on the generation of a cancer can be divided into 

Oncogenes (where a mutation has activated a gene whose function contributes to the tumorigenic state)

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Tumor suppressors (where a mutation has inactivated a gene whose function antagonizes the tumorigenic state).

Causes of cancer 

Substances that cause cancer are called carcinogens.

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Since the development of malignancy is a complex multistep process, many factors may affect the likelihood that a cancer may develop. 

Mutagens.

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Tumor promoters.

Properties of cancer cells   

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Lacks density-dependent inhibition. Reduced requirement of growth factors. Continuous auto stimulation of cell division – autocrine growth stimulation. Less adhesive. Rounder than normal cells. Lacks contact inhibition. Secrete proteases that digest ECM, allowing the cells to invade adjacent normal tissue. Secrete growth factors that promote the formation of new blood vessels (angiogenesis). Fail to differentiate normally. Fail to undergo apoptosis.

Tumor viruses 

Members of several families of animal viruses are capable of directly causing cancer. 

Hepatitis B & C viruses (liver cancer).

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Papillomavirus (cervical cancer).

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Epstein-Barr virus (Burkitt’s lymphoma & nasopharyngeal carcinoma).

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Kaposi’s sarcoma associated herpes virus ( Kaposi’s sarcoma).

Hepatitis B virus 

Has the smallest genome (3kb) of all animal DNA viruses.

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Specifically infect liver cells of many species.

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Infection results in acute liver damage.

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In 5-10% acute infection is not resolved and chronic infection of the liver develops.

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Such chronic infection is associated with more than a hundred fold increases risk of liver cancer.

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Infection common in Asia & Africa.

Hepatitis B virus… 

Cell transformation is mediated by a viral gene (X gene) that affects expression of a variety of cellular genes that drive abnormal cell proliferation and survival.

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Development of cancer induced by continual proliferation of liver cells that result from chronic tissue damage and inflammation.

Hepatitis C virus 

RNA virus with a genome of approximately 10 kb

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Can establish chronic liver infections that are associated with a high risk of cancer.

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Cell proliferation in response to chronic inflammation is a major contributor to carcinogenesis.

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It is also possible that some hepatitis C virus proteins directly stimulate proliferation of infected liver cells.

SV40 & Polyomavirus 

Not associated with human cancers.

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Critically important as models for understanding the basis of cellular transformation.

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Transformation by these viruses has been found to result from the expression of the same viral genes that function in early stages of lytic infection.

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Both SV40 & polyomavirus early proteins induce transformation by interacting with host proteins that regulate cell proliferation.

Papillomaviruses 

Small DNA viruses.

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Induce both benign and malignant (Cervical and anogenital) tumors in humans and various other animal species.

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Approximately 60 different types which infect epithelial cells of various tissues have been identified.

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Cell transformation induced by two early genes (E6 & E7), interacting with Rb abd p53.

Adenoviruses 

DNA virus.

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Not associated with natural human cancers, widely used for studies.

Herpesviruses 

Kaposi’s sarcoma-associated herpesvirus.

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Epstein-Barr virus (affects lymphocytes).

Retroviruses 

Human T-cell lymphotropic virus Type I (HTLV – I) : adult T-cell leukemia.

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HIV: does not cause cancer directly, but people infected with HIV have a higher risk of cancer.

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Rous sarcoma virus (RSV).

Genetic abnormalities triggering carcinogenesis 

Cell proliferation triggered independent of normal proliferation signals.

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Variety of mechanisms 

Mutations or overproduction of receptors or transducing proteins.

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Abnormalities of tumor suppressor genes.

Tumor suppressor genes 

Genes that are responsible for suppressing cell division.

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Abnormalities result in uncontrolled cell division.

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Result in cancer through failure of the host to destroy the abnormal cells.

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These are recessive mutations.

Tumor suppressors… 

Hereditary tumors 

Retinoblastoma gene (RB1).

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Wilm’s tumor (WT1).

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Familial polyposis (APC).

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Familial melanoma (CDKN20).

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Familial breast and ovarian cancer (BRCA1 & BRCA2).

Tumor suppressors… 

p53 Suppressor gene. 

p53 protein suppresses the cell cycle with multiple complex activities.

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It detects DNA lesions like nucleotide mismatches, DNA strand breaks etc.

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On detection of DNA lesions, cell cycle is halted at G1 phase and either repair mechanisms or apoptosis is triggered.

Oncogenes 

Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation and survival.

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Studies of tumor virus revealed specific genes (oncogenes) capable of inducing cell transformation.

Oncogenes… 

Genes that cause malignant transformation of normal cells.

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They are constantly associated with malignancies and may be either of cellular or retroviral origin.

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More than one oncogene is abnormally active in cancer.

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Multiple interactions among oncogenes that are necessary for cell division results in the activation of many otherwise normal oncogenes.

Oncogenes…   

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Retroviral oncogenes (v-onc). Cellular onocogenes. Inhibitory genes: produce proteins that inhibit cell proliferation. Abnormalities lead to abnormal cell proliferation. Proto-oncogenes (c-onc): control proliferation and differentiation in normal cells. RNA from transforming retroviruses is homologous with various proto-oncogenes  

Highly conserved through evolution. Codes for proteins that are differentially expressed during the cell cycle or at specific stages of development of a tissue.

Thank you ….