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Understanding Cancer

occurs when a single cell acquires the ability to reproduce aggressively and to invade other tissues. INVASIVENESS Greeks: invasive crab claws

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)

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

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

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

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

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 Circulation 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

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

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

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

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

Cancer is 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. Any substance or radiation that is an agent directly involved in causing cancer is called a carcinogen.

Chemicals Polycyclic Aromatic Hydrocarbons (PAH) 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

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.

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

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.

Physical Agents Metals


Arsenic Nickel Cadmium Chromates

Fibers and Dust


Asbestos Silica Wood Dust

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 310% of all 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 over-expression 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.

Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.

Mutations
The errors which cause cancer are self-amplifying and compounding, for example:
A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly. A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts. A further mutation may cause loss of a tumor suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal. A further mutation in signaling machinery of the cell might send errorcausing signals to nearby cells.

Error-correcting machinery DNA Repair Genes

Mutations
The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution drives progression towards more invasive stages.

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.

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.

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

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)

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.

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 immortal. 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.

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.

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. Cancer cells circulate through the bloodstream

Stages of tumor development


A malignant tumor develops across time. This tumor develops as a result of four mutations, but the number of mutations involved in other types of tumors can vary. We do not know the exact number of mutations required for a normal cell to become a fully malignant cell, but the number is probably less than ten.

1. The tumor begins to develop when a cell experiences a mutation that makes the cell more likely to divide than it normally would.

2. The altered cell and its descendants grow and divide too often, a condition called hyperplasia. At some point, one of these cells experiences another mutation that further increases its tendency to divide.

3. This cell's descendants divide excessively and look abnormal, a condition called dysplasia. As time passes, one of the cells experiences yet another mutation.

4. This cell and its descendants are very abnormal in both growth and appearance. If the tumor that has formed from these cells is still contained within its tissue of origin, it is called in situ cancer. In situ cancer may remain contained indefinitely.

5. If some cells experience additional mutations that allow the tumor to invade neighboring tissues and shed cells into the blood or lymph, the tumor is said to be malignant. The escaped cells may establish new tumors (metastases) at other locations in the body.

Flow Cytometry in Oncologic Diagnosis Biomarkers for Cancer Diagnostics Molecular Diagnostics Molecular Cytogenetics

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.

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).

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. 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.

DETECTION BIOMARKERS DIAGNOSTIC BIOMARKERS PROGNOSTIC BIOMARKERS PREDICTIVE BIOMARKERS

Genomic and proteomic technologies


DNA and tissue microarray Two-dimensional gel eletrophoresis Mass spectrometry Protein assays coupled with advanced bioinformatic tools,

Methods

Molecular cytogenetics involves the combination of molecular biology and cytogenetics. Techniques Fluorescence in situ hybridization Spectral Karyotyping Comparative Genomic Hybridization

Dichloroacetate
Two major pathways for extracting ATP from sugar molecules: Glycolysis- two ATP molecules per sugar molecule, without oxygen Glucose oxidation - takes byproduct of glycolysis, pyruvate, and burn to produce 36 ATP, with oxygen Glycolysis takes place in the cytoplasm while glucose oxidation takes place in the mitochondria. A gate-keeeping enzyme called Pyruvate Dehydrogenase Kinase(PDK) regulates the flow of pyruvate into the mitochondria. If PDK is active, it suppresses the transport of pyruvate which then forces the cell to rely on glycolysis. Dichloro Acetate (DCA) inhibits PDK, forcing cells to use glucose oxidation (making the cancer cells uncomfortable, since they arise in hypoxic environments meaning, the cancer cells tend to suppress the mitochondria to keep the level of oxygen low). And by tampering with the cancer cells system, it may activate cell suicide.

Mitochondria - a primary regulator of cell suicide

- 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 - Infection - Fatigue - Loss of appetite - Swelling around the site of surgery - Bleeding

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

- refers to the administration of drugs that stop the growth of cancer cells by killing them or preventing them from dividing 2 kinds of Chemotherapy - Palliative Chemotherapy - Adjuvant Chemotherapy
Example: Alkylating agents

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

- 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

-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). -When photosensitizers are exposed to a specific wavelength of light, they produce a form of oxygen that kills nearby cells.

Side Effects -Burns -Swelling -Pain -Painful breathing (temporary) -Coughing (temporary)

Cancer Research
Causes of Cancer Genetics how genetics take part in cancer research Diet researching how diet affects the probability of people getting cancer Environmental Factors other factors that cause cancer Oncogenomics The study of identifying all genes which may cause cancer. The goal of oncogenomics is to provide new insights in cancer diagnosis Cancer Treatments Development of these treatments are currently underway so that they can be more effective.

Lab rats Treatment on a mouse does not necessarily reflect that of a person's. Funding Research is always slow moving because of lack of funds. Bigger isn't always better Break through ideas are frequently scoffed at by large institutions. Smaller but less effective ideas are more accepted by the researching community.

Community Nutrition - Community nutritionists ensure that what you eat is good for your health. Materials Engineering - Proper management of wastes and other carcinogenic materials can help reduce the percentage of the population that is afflicted with cancer. Psychology - Any form of stress such as trauma, unemployment, divorce, separation, family, and other professional problems can occur in the first few months or years in the beginning of the disease. Biology - Biology majors can study the cancer effects on animals and learn how detect these symptoms earlier. Chemistry - Chemistry deals with the composition of cancer prevention drugs and how they can be further improved. Molecular Biology and Biotechnology - Gene therapy and other treatments could benefit many cancer patients. With MBB researchers, the development of these treatments are made possible.

1 out of 3 people are afflicted by cancer Human testing is risky and costs a lot of money to experiment on cancer treatments With proper funding, these cancer treatments may be able to have the exact effects that we want

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

http://sciencepark.mdanderson.org/fcores/flow/files/Oper ation.html http://www.cancer.gov/cancertopics/understandingcancer/ moleculardiagnostics/MOLEDIAG.PDF http://www.ncbi.nlm.nih.gov/pubmed/16555974 http://www.canceritspersonal.com/consumer/personalized Medicine/WhatAreBiomarkers.aspx?source=google&HBX_P K=s_+cancer++diagnosis++biomarker&HBX_OU=50&o=595 67340|235712540|0&skwid=43700003034512213 http://atlasgeneticsoncology.org/Deep/ComparCancerCyto gID20011.html http://www.expertreviews.com/doi/pdf/10.1586/14737159.4.1.71

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