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Oncology
Understanding Cancer

Cancer
occurs when a single cell acquires the ability to reproduce aggressively and to invade other tissues. Cancer is fundamentally a disease of failure of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered. INVASIVENESS Greeks: invasive crab claws

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Molecular Tools in Cancer Research


Human Genome Single-Nucleotide Polymorphisms (SNP) (variation of a single base pair) Engineering Genes Gene Regulation Profiling Tumors Cancer Proteome Proteome (the entire complement of proteins that are expressed by the genome of a cell, tissue, or organism) Modeling Cancer in Vivo Models of Recessive Gene Mutations in Cancer Gene Knockout Technology (inactivation of genes)

Biology of Tumors
Parts of a Tumor: -Malignant tumor cells : neoplastic cells (abnormal and purposeless augmentation of cells/cell growth) -Stroma: support structure containing blood vessels for oxygen & nutients and immune/inflammatory cells Hypoxic/Deprived of oxygen (Hypoxic-Necrotic

microenvironment )

Tumor Pathophysiology
-result of interactions in the Tumor (cells, surrounding matrix, local microenvironment) -governs: tumor growth, invasion, metastasis and responses to various therapies

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Biology of Tumors

hypoxic (light purple areas) and later necrotic (gray areas)

Biology of Tumors
3 kinds of Tumor: a)Benign - non-invasive; well-defined growth with smooth boundaries b)Malignant - locally invasive; irregular boundaries and invades the surrounding tissue (CANCEROUS) c)Metastatic - travels to other parts of the body (CANCEROUS); *kills the majority of cancer patients

Tumor Progression -depends on the number of mutations

-primary tumors possess stem cells

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Tumorigenesis
1) Cell Transformation *Proto-oncogenes (normal cells) to Oncogenes (mutated cells) dysregulated cell growth & increased life span loss of tumor suppressor genes *Normal Cell ratio (Cell division: Apoptosis)

DNA damage in sensing and repair pathways

2) External Barriers for Metastasis Physical barriers (ECM or Extracellular Matrix and BM or Basement Membranes) Hypoxia (limited oxygen) and limited nutrients changes in pH immunologic responses

Intracellular Signaling & Angiogenesis


Intracellular Signaling
controls cell growth, metabolism, death, differentiation, movement, and invasion transition to malignancy, alterations in key receptors and signaling pathways occur usually a result of receptor mutations Example: Angiogenesis (VEGF Factor)

Angiogenesis
formation of a new blood supply from pre-existing vasculature angiogenic switch VEGF (Vascular Endothelial Growth Factor)

*formation of a premetastatic niche-malignant tumor, and Angiogenesis is essential for the growth of metastatic tumor cells

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Metastasis

transfer of tumor cells from a primary site to a secondary site Greek word meaning "change of state Stages of Metastasis: 1) Invasion: entry to other tissues Matrix attachment

Action of Proteases (enzymes that degrade proteins)


2) Intravasation: entry to the circulation; mutated vasculature 3) Survival in the Circulatio n subjected to immune attack, circulatory forces, and anoikis (apoptosis by loss of adhesion) platelet binding and Tumor Cell Emboli 4) Extravasation: exit to the circulation; normal vasculature 5) Proliferation and Angiogenesis : formation of new tumor *Circulation: Lymphatic or Blood system

Metastasis Multi-step
*Metastasis of Metastases : due similar microenvironmental stresses or barriers

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Organ Specificity of Tumor Metastasis


Determined by: Blood flow & tissue-specific factors (seed-and-soil Theory) 1) Bone osteoblastic: advanced prostate cancer osteolytic: breast cancer or multiple myeloma 2) Brain breastcancer, lung cancer, and melanoma 3) Lung sarcoma, breast, melanoma, gastrointestinal, and kidney cancers 4) Liver breast, lung, and pancreatic cancers

Cancer Immunology
Different immune response as a result of being originally a normal cell Tumor & Oncogenic Pathways inhibit effecter functions of immune system and alter immunologic activity to promote tumor growth and development. Tumor-Specific Antigens (TSAs ) Translated antigens from genetic & epigenetic changes capable of being recognized by the immune system Toleragenic DCs & inactivated Tumor T -Cells in an oncogenic environment

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Myths about the causes of Cancer


Viruses Infectious Agents Breakdown in Immunity (With Age, lowers immunity) Genetic Mutations

Genetics and Causes

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Causes
Cancers are primarily an environmental disease with 90-95% of cases attributed to environmental factors and 5-10% due to genetics. Environmental, as used by cancer researchers, means any cause that is not genetic, not merely pollution.

Common environmental factors that contribute to cancer death include tobacco (25-30%), diet and obesity (30-35%), infections (15-20%), radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.

Environmental Factors
Chemicals
Polycyclic Aromatic Hydrocarbons potent atmospheric pollutants, occur in oil, coal, and tar deposits, produced as byproducts of fuel burning (whether fossil fuel or biomass), also found in food cooked at high temperatures Aromatic Amines found in the plastic and chemical industries, as byproducts of the manufacturing of compounds such as polyurethane foams, dyes, pesticides, pharmaceuticals and semiconductors; also found in environmental pollution such as diesel exhaust, combustion of wood chips and rubber, tobacco smoke and grilled meats and fish Benzenes natural constituent of crude oil, important industrial solvent and precursor to basic industrial chemicals including drugs, plastics, synthetic rubber, and dyes Aflatoxins naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide. Alcohol is associated with an increased risk of a number of cancers. About 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol. Chemotherapeutic Agents

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Environmental Factors
Diet, physical inactivity, and obesity:

3035% of cancer cases.

Diets that are low in vegetables, fruits and whole grains, and high in processed or red meats are linked with a number of cancers. Physical inactivity is believed to contribute to cancer risk not only through its effect on body weight but also through negative effects on immune system and endocrine system. In the United States excess body weight is associated with the development of many types of cancer and is a factor in 14 20% of all cancer death.

Environmental Factors
Infection: 18% of all cancers worldwide
Viruses human papillomavirus Epstein-Barr virus Kaposi's sarcoma herpesvirus hepatitis B and hepatitis C viruses Human T-cell leukemia virus-1 Bacteria Helicobacter pylori Parasites Schistosoma haematobium liver flukes Opisthorchis viverrini Clonorchis sinensis

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Environmental Factors
Radiation: Up to 10% of invasive cancers
Ultraviolet emitted by the sun Ionizing medical imaging, and radon gas Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer.

Environmental Factors
Physical Agents Metals
Arsenic Nickel Cadmium Chromates

Fibers and Dust


Asbestos Silica Wood Dust

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Genetic Factors
Hereditary cancers are cancers that are primarily caused by an inherited genetic defect. Hereditary cancer tends to occur at an abnormally early stage in life (genetic predisposition) Less than 0.3% of the population are carriers of a genetic mutation which has a large effect on cancer risk. They cause less than 3 10% of all cancer

Genes Involved in the Development of Cancer


The affected genes are divided into two broad categories. Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate overexpression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

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Normal cells
Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by external growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit cell suicide (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.

Cancer
All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical protein must be damaged in each of those mechanisms. These proteins are damaged when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, called hallmarks.

Comparison of Normal and Cancer Cells


Normal cells
Growth and division controlled by external growth factors. Damaged cells are stopped from dividing until they are repaired. Irreparably damaged cells undergo apoptosis. Divide a limited number of times. Part of a tissue structure; remain where they belong. Need a blood supply to grow.

Cancer cells
Self-sufficiency in growth signals Insensitivity to anti-growth signals Evade apoptosis Limitless reproductive potential Sustained angiogenesis Tissue invasion and metastasis

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The Hallmarks of Cancer


All cancers share six common traits ("hallmarks") that govern the transformation of normal cells to cancer (malignant or tumor) cells.
1) cancer cells stimulate their own growth 2) they resist inhibitory signals that might otherwise stop their growth 3) they resist their own programmed cell death (apoptosis) 4) they stimulate the growth of blood vessels to supply nutrients to tumors ( angiogenesis) 5) they can multiply forever 6) they invade local tissue and spread to distant sites (metastasis)

The Hallmarks of Cancer


Self-sufficiency in growth signals Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply. Insensitivity to anti-growth signals Cancer cells are generally resistant to growth-preventing signals from their neighbours. Evading apoptosis

Apoptosis is a form of programmed cell death (cell suicide), the mechanism by which cells are programmed to die in the event they become damaged. Cancer cells characteristically are able to bypass this mechanism.

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The Hallmarks of Cancer


Limitless reproductive potential Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60-70 doublings, at which point they reach a stage of senescence. This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10-7) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized. The counting device for cell doublings is the telomere, which loses DNA at the tips of every chromosome during each cell cycle. Many cancers involve the upregulation of telomerase, the enzyme that maintains telomeres.

The Hallmarks of Cancer


Sustained angiogenesis Cancer cells initially lack angiogenic ability, limiting their ability to expand. In order to progress, they must develop a blood supply. Angiogenesis is balanced by inducers and inhibitors. Angiogenesis is the process by which new blood vessels are formed. Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients.

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The Hallmarks of Cancer


Tissue invasion and metastasis Cancer cells break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) to distant body parts. Circulate through the bloodstream

DIAGNOSING CANCER

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Diagnosis Techniques
Flow Cytometry in Oncologic Diagnosis Molecular Diagnostics

Biomarkers for Cancer Diagnostics


Molecular Cytogenetics

Flow Cytometry in Oncologic Diagnosis


Cytometry is the quantitative analysis of single cells

Flow Cytometry is the characterization of individual cells as they pass at high speed through a laser beam.
While a hematologist can count 200 cells in less than a minute by hand (hemocytometer) on a stage microscope, a flow cytometer can discriminate cells at speeds up to 70,000 cells/second. Application: lymphomas & leukemias flow cytometry may also be use as part of the stem cell transplantation process. Flow cytometry can also be used to measure the amount of DNA in cancer cells. In this case, the cells are treated with special light-sensitive dyes that react with DNA. For patients with breast, prostate or bladder cancer, an abnormal amount of DNA may indicate a recurrence.

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HOW IT WORKS
A flow cytometer sorts cells by vibrating the solid flow stream with a quartz crystal tuned to an exact frequency to form stable drops. The physical (morphological) profile of a cell can be observed by combining forward light scatter (FS) and orthogonal or side light scatter (SSC).

Cancer Biomarkers
What are Biomarkers? Biomarkers are substances found in blood, other bodily fluids, or tissues that can help tell us a lot about certain types of cancers.1 They are like a map or a signature that doctors may use to guide how to treat some cancers. They may help predict your risk for some cancers or may help tell us if a treatment may be more or less likely to work.1 Biomarkers have been found for breast, colorectal, lung, and prostate, among other tumor types.2,3 Some markers have been found only in one type of cancer so far. Others may be present in different types of cancer.4 For example, the gene HER-2 has been found in breast and stomach cancer.4

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Types of Biomarkers
DETECTION BIOMARKERS DIAGNOSTIC BIOMARKERS PROGNOSTIC BIOMARKERS PREDICTIVE BIOMARKERS

Techniques used in development of cancer biomarkers


genomic and proteomic technologies
DNA and tissue microarray, two-dimensional gel eletrophoresis, mass spectrometry protein assays coupled with advanced bioinformatic tools,

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Molecular Diagnostics

Molecular Diagnostics

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Molecular Diagnostics

Molecular Diagnostics

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Molecular Diagnostics

Molecular Diagnostics

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Molecular Cytogenetics
Molecular cytogenetics involves the combination of molecular biology and cytogenetics. Techniques: fluorescence in situ hybridization Spectral Karyotyping

Comparative Genomic Hybridization

TREATMENTS

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SURGERY
- involves the physical removal of the tumor, typically along with some of the surrounding, apparently healthy tissue. - generally performed for limited-stage (stage I or sometimes stage II)

Examples: - Lobectomy (lung cancer) - Masectomy (breast cancer)


Side Effects: - Pain - Fatigue - Loss of appetite - Swelling around the site of surgery - Bleeding - Infection

Radiation Therapy
Radiation therapy uses high-energy X-rays or other types of radiation to kill cancer cell

Examples: Brachytherapy External beam radiation therapy or teletherapy Side Effects: - Fatigue - Skin problems (may appear red, sunburned, tan or irritated) - Loss of appetite - Hair loss (occurs at the site being treated)

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Chemotherapy
refers to the administration of drugs that stop the growth of cancer cells by killing them or preventing them from dividing. Side Effects: - Anemia - loss of appetite & weight changes - Fatigue - dry skin - Hair loss - sore mouth, gums and throat - Nausea and vomiting - low white blood cells count

2 kinds of Chemotherapy - Palliative Chemotherapy - Adjuvant Chemotherapy Example: Alkylating agents

Biological Therapy
- form of treatment that uses portions of the body's natural immune system to treat a disease. - involves the use of substances called biological response modifiers (BRMs)
Example: Interleukin-2 Side Effects: - Fever - Diarrhea - Muscle aches - Weakness - Loss of Appetite - Nausea and vomiting

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Photodynamic Therapy
- treatment that uses a drug called a photosensitizer or photosensitizing agent (porfimer sodium), and a particular type of light (laser or other sources of light). Side Effects: - Burns - Swelling - Pain - When photosensitizers are exposed to a specific wavelength of light, they produce a form of oxygen that kills nearby cells. - Painful breathing (temporary) - Coughing (temporary)

References:
Abeloff, M. D., Armitage, J. O., Niederhuber, J. E., Kastan, M. B., & McKenna, W. G. (Eds.). (2008). Abeloff's Clinical Oncology. Churchill Livingstone: Elsevier Inc. www.Biointeractive.org 2003 Holiday Lectures-Learning from Patients-Howard Hughes Medical Institute (HHMI) www.AACR.org www.biooncology.com "Detailed Guide: How Is Cancer Treated." 04 AUG 2007. American Cancer Society. Accessed 06 Dec 2008.

"Chemotherapy PDQ: Treatment Overview." 27 Feb 2007. National Cancer Institute. Accessed 06 Dec 2008.
http://cancer.about.com/od/treatmentoptions/a/options.htm

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References:
http://sciencepark.mdanderson.org/fcores/flow/files/Operation.html http://www.cancer.gov/cancertopics/understandingcancer/moleculardiagnostics/M OLEDIAG.PDF http://www.ncbi.nlm.nih.gov/pubmed/16555974

http://www.canceritspersonal.com/consumer/personalizedMedicine/WhatAreBiom arkers.aspx?source=google&HBX_PK=s_+cancer++diagnosis++biomarker&HBX _OU=50&o=59567340|235712540|0&skwid=43700003034512213


http://atlasgeneticsoncology.org/Deep/ComparCancerCytogID20011.html http://www.expert-reviews.com/doi/pdf/10.1586/14737159.4.1.71

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