Cancer

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Cancer affects one in three people; estimated 569,490 Americans would die of cancer in 2010

Worldwide incidence of cancer is about 10 million cases/year

Cancer statistics

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Cancer is a group of diseases characterized by unregulated cell growth

Invasion of adjacent tissues Spread of cells from the site of origin

(primary site) to other sites in the body (metastases

What is cancer?

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Carcinogenesis◦Process of inducing cancer◦Cancer is essentially a disease at the level of DNA, i.e., the molecular biology of cancer

What is cancer?

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Carcinomas: epithelia [80% of cancers]◦ Squamous cell carcinomas [protective cell

layers such as skin, lung, esophagus, cervix, etc. Think what these cells are exposed to in the colon,

bile duct, lungs and skin] Adenocarcinomas [secretory epithelia such

as lung, colon, breast, pancreas, stomach, esophagus, prostate, endometrium, ovary, etc.]

Cancer is a group of diseases

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Sarcomas: connective [mesenchymal] tissue [1% of cancers]◦ Osteosarcomas, fibrosarcomas, chondrosarcomas,

etc. Hematopoietic tumors: the blood-forming

tissues and immune tissues◦ Leukemias and lymphomas, etc.

Neuroectodermal tumors: nervous tissue◦ Gliomas, etc

Cancer is a group of diseases

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Cell division is usually a closely regulated process & cell cycle regulatory controls are lost in cancer

Unregulated cell growth

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Cancer is a disease of multicellularity [Aggregate number of cells formed during an average human lifetime: 1016]. ◦ Each time a cell divides there are many things

that can go wrong...more about the regulation of cell division later on...

Cell division is a normal biological process [growth, development, repair] but one that creates a risk of cancer]

Unregulated cell growth

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¨ 220 cells are almost undetectable

¨ 230 cells is a small lump (about a 1 cm mass)¨ More than 1 billion cell clumped together

¨ 240 cells is a large tumor A dime is 1.5 cm

Uncontrolled Cellular Growth

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Malignant tumors: do spread or metastasize◦ Disrupting other tissues & competing for nutrients

and oxygen

Invasion and spread of cells

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Cancer cells vs. normal cells

Normal Cells

In cell culture conditions: cell contact inhibition: ◦ Cell surface receptors

recognize contact with other cells with contact triggering the internal pathways that inhibit division by arresting the cell cycle, usually in the G1phase

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Cancer cells vs. normal cells

Cancer Cells

In cell cultures in the lab, cell division continues until all the cells are in contact with their neighbors in a continuous, unbroken, single layer when division then stops ◦ Removal of cells cause

some cells to divide in order to restore the continuous layer

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Contact Inhabition

Normal Cells Cancer Cells

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Different degrees of abnormality Normal hyperplasiametaplasia dysplasia

neoplasia metastasis

Cancers develop progressively

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Growth signal autonomy Evasion of growth inhibitory signals Evasion of apoptosis Unlimited replicative potential Angiogenesis Invasion and metastasis

The six hallmarks of cancer

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Carcinogens vs. mutagens ◦ The International Agency for Research on Cancer

lists about 100 agents that are classified as "carcinogenic to humans"

Most agents that cause cancer [carcinogens] are agents that cause alterations to the DNA or mutations [mutagens]◦ Note: not all carcinogens are mutagenic;

that is, some carcinogens promote tumors via non-genetic mechanisms

Evidence suggests that cancer is a genetic disease at the cellular level

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Mutations come in several varieties [e.g., point mutations, chromosomal translocations] and may affect protein structure and function; more on mutations later

Evidence suggests that cancer is a genetic disease at the cellular level

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Any alteration in these processes can alter cell number and remember, cancer is a failure of cells to control their replication

Cell growth: cell division or mitosis: the human body is constantly making more cells in the processes of growth and repair

Apoptosis (programmed cell death or cell suicide): infected, damaged or "old" cells can "off" themselves for the good of whole body◦ Think about the peeling skin that comes with a

bad sunburn...

Growth, apoptosis, and differentiation regulate cell numbers

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Differentiation (a process in which changes in gene expression establishes cells with specialized structure and function; e.g., stem cells become nervous or muscle cells)

Growth, apoptosis, and differentiation regulate cell numbers

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Proto-oncogenes (oncos, tumor): a normal gene that encodes various kinds of proteins that stimulate cell division◦ Mutated proto-oncogenes ("good genes gone

bad") become oncogenes [Note: this was a huge development in the mid-1970s because for the first time it suggested that the normal genome in a cell, under certain conditions, could cause cancer]

Oncogenes and tumor suppressor genes

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Oncogenes and Tumor Suppressor Genes

Oncogene

Oncogenes: "stuck accelerators" (control mechanisms that initiate cell division become hyperactive)

Tumor suppressor genes: "failed brakes" (control mechanisms that suppress cell division)

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Random, unavoidable events in cell division [DNA replication is remarkably precise: only one in10 billion nucleotides! This accuracy is due to proofreading and repair enzymes, but alas, there are mistakes, if ever so rare]

Heredity [gene variations or alleles]: pick your parents wisely! Susceptibility to cancer, both in general and for particular forms of cancer [e.g., breast cancer] is hereditary

Influential factors in human carcinogenesis

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Enviroment [physical environment + lifestyle (diet, reproductive habits, tobacco, etc.); the dominant determinant in country-to-country cancer incidences]◦ Physical agents [UVB radiation, ionizing radiation,

X-rays; The Seattle Times [12-15-09]: CT Scans Linked to Surge in Cancers“

◦ Chemical agents [coal tar, asbestos, hydrocarbons that arise from the incomplete combustion of organic mater]

Influential factors in human carcinogenesis

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Viral [At one time viruses were thought to cause many types of cancer; today, it is known that the majority of cancers have nothing to do with viruses...]

Influential factors in human carcinogenesis

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Reproductive life◦ Having children reduces risk of breast cancer

Stone age women may have had about 150 menstrual cycles due to later menarche, earlier menopause, more pregnancies and more lactation

A modern woman, even if she has two or three children, might have two or three times this number of cycles [Why We Get Sick, Nesse & Williams]

Influential factors in human carcinogenesis

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Diet: salt? alcohol? smoked meats? Smoking Additional influences

◦ 1. Error in DNA replication [see above, random, unavoidable events]

◦ 2. Free radicals ["unpaired electrons" generated whenever we use oxygen, which is 24/7]

Influential factors in human carcinogenesis

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Cut [surgery], poison [chemotherapy], burn [radiation], and pray

Principles of conventional cancer therapies

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Chemotherapy◦ Cause severe DNA damage and trigger apoptosis

Why loss of hair, nausea, anemia with chemotherapy?

Principles of conventional cancer therapies

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“A Formal Process of Trial and Error” Phases

◦ Phase I: safety [20-100 patients]◦ Phase II: efficacy [several hundred]◦ Phase III: efficacy often tested against

conventional treatments [100s-1000s]

Clinical Trials:

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Molecules of fame◦ Phosphorylation, Kinases, and phosphatases

Phosphorylation: adding a phosphate group to a molecule where the added phosphate either stimulates or inhibits the activity of proteins, often enzymes; a very common characteristic of cell signaling (transduction) pathways]

Kinases: enzymes that add phosphates to target proteins

Phosphatases: enzymes that remove phosphates from target proteins, often enzymes

The role of molecular targets in cancer therapies

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Ras genes and proteins◦ Cells generally do not begin division until they receive a

signal [e.g., growth factor] from outside themselves. Once this growth factor binds to a cell, a series of chemical reactions inside the cell triggers cell division. One of the key links in this "cascade" of reactions is a protein called Ras that acts as an "on/off" switch to the cell cycle. Ras is coded for by the ras genes, a family of genes that are involved in cellular signaling [ras = rat sarcome]. When mutated, ras tells the cell to divide continuously no matter what the signal is from the outside. Note: genes are usually in italics and their protein products are in normal roman font. Human genes are capitalized in italics [e.g., MYC] and its protein product is MYC

The role of molecular targets in cancer therapies

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Tumor suppressor genes/proteins: p53 and retinoblastoma gene [Rb]◦ p53 [p= protein, 53=molecular mass (53

kilodalton); encoded by the TP53 genes on chromosomes 17]: the "guardian of the genome" since it can stop the cell cycle upon recognizing DNA damage, activate repair proteins and initiate apoptosis

◦ Rb: retinoblastoma [Rb] tumor suppressor gene and protein

The role of molecular targets in cancer therapies

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Cancer Genome Anatomy Project [CGAP; http://cgap.nci.nih.gov/cgap.html]

The introduction of cancer genomics

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Colorectal cancer [third leading cancer killer in U.S.]: death rate " down 20% in last 10 years;◦ By 2020, the rate could be half what it was in

2000 [The Seattle Times 12-8-09]

Good News

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