2. Cellular Aberration


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For MMC-CN Students. Lectured by Prof. Julius Floresta.

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2. Cellular Aberration

  1. 1. 2. CELLULAR ABERRATIONThe Biology of CancerProf. Flas Julius Flores
  2. 2. TERMS Cancer – a disease process that begins when an abnormal cell is transformed by the genetic mutation of the cellular DNA In cancer, the abnormal cell forms a clone and begins to proliferate abnormally, ignoring growth-regulating signals in the environment surrounding the cell Hyperplasia Metaplasia Dysplasia Anaplasia Neoplasia – new growth; tumor; can be benign or malignant; uncontrolled cell growth that follows no physiologic demand
  3. 3. TERMS Benign – not malignant; an abnormal growth that is stable, treatable and generally not life-threatening Malignant – cancerous; cells that are invasive and tend to metastasize, uncontrollable or resistant to therapy; rapidly spreading Invasion – refers to the growth of the primary tumor into the surrounding host tissues Metastasis – the dissemination or spread of malignant cells to distant sites by direct spread of tumor cells to body cavities or through lymphatic and blood circulation
  4. 4. Characteristics of Benign and Malignant NeoplasmsCharacteristics Benign MalignantCell characteristics Well-differentiated that Cells are undifferentiated resemble normal cells of and often bear little the tissue from which the resemblance to the tumor originated normal cells of the tissue from which they arose Grows at the periphery and sends out processesMode of growth Tumor grows by that infiltrate and destroy expansion and does not the surrounding tissues infiltrate the surrounding tissues; usually Variable and depends on encapsulated level of differentiation; the more anaplastic theRate of growth Usually slow tumor, the faster its growth
  5. 5. Characteristics of Benign and Malignant NeoplasmsCharacteristics Benign MalignantMetastasis Negative Gains access to the blood and lymphatic channels and metastasizes to other areas of the body Often causes generalizedGeneral effects Is usually a localized effects, such as anemia, phenomenon that does not weakness, and weight loss cause generalized effects unless its location interferes with vital functions Often causes tissue damage Does not usually cause as the tumor outgrows itsTumor destruction tissue damage unless its blood supply or encroaches location interferes with blood on blood flow to the area; flow may also produce substances that cause cell damage Does not usually causeAbility to cause death death unless its location Usually causes death unless interferes with vital functions growth can be controlled
  6. 6. TERMS Carcinoma – term used for malignant tumors of epithelial in origin (bronchogenic carcinoma, invasive ductal carcinoma, endometrial carcinoma, adenocarcinoma, squamous cell carcinoma, basal cell carcinoma) Sarcoma – term used for malignant tumors of mesenchymal/connective tissue in origin (rhabdomyosarcoma, liposarcoma, leiomyosarcoma, angiosarcoma) Note: benign tumors usually end with the suffix “oma”, except for lymphoma, hepatoblastoma, neuroblastoma, myeloma, melanoma. These are already malignant
  7. 7. TERMS Solid tumor – an abnormal mass that does not contain cyst or liquid.Example of conditions : breast cancer, colorectal , neuroblastoma, Wilms tumor, uterine, brain, lung cancer liquid – mass that contain liquid.Example: Lymphomas ( Hodgkin and non- Hodgkin), leukemia
  8. 8. Fibroadenoma – solid tumorFribrocystic change, breast –cystic/liquid tumor
  9. 9. TERMS Angiogenesis – the growth of new capillaries from the host tissue by the release of growth factors and enzymes such as vascular endothelial growth factor (VEGF) Mutation – an alteration in a DNA nucleotide sequence – the order of the four bases adenine (A), cytosine (C), thymine (T), and guanine (G) Mutations can alter both the sequence of a gene and its regulatory sites Tumor suppressor genes – normally suppress or negatively regulate cell proliferation by encoding proteins that block the action of growth-promoting proteins
  10. 10. TERMS DNA-repair genes – the “caretaker genes” – genes involved in controlling or regulating genetic instability to ensure integrity of genetic information Oncogenes – genes that encode proteins (oncoproteins) whose action promotes cell proliferation
  11. 11. TUMOR SUPPRESSOR GENES Hallmark characteristic of a mutated tumor suppressor gene is loss of function through:1. Loss of genetic material2. Loss of information Examples:a. APC, MEN1, p53, RB, and WT1 – affect DNA transcriptionb. BRCA1 and BRCA2 – play roles in DNA repairc. RB, p16 and TP53 – critical for the operation of the cell cycle, suggesting that many tumor suppressor genes act as “gatekeeper” genes
  12. 12. SOME EXAMPLES OF GENES IN CANCERSUSCEPTIBILITY ALDH2 – alcohol-related cancers APC – colorectal cancer CCND1 – head and neck cancer COMT – breast cancer CYP1A1 – lung, oral, and breast cancers, childhood leukemias GSTM1 - bladder and breast cancers; lung cancers HRAS – breast, ovarian, lung and colorectal cancer risk LTA – myeloma MCIR – melanoma
  13. 13. THEORIES AND RESEARCH MODELS OF TUMORDEVELOPMENTKey Points of Major of TumorgenesisTheory Key PointsMultistep Initiation: •Stem cell becomes initiated by acquiring one or more mutations, leading to partial escape from normal homeostatic control •Genetic mutations or epigenetic events responsible •Irreversible Promotion •Initiated cell stimulated to proliferate but not terminally differentiate •Initiated cell acquires further genetic changes required for neoplasms •Interruptible and sometimes reversible Progression •Malignant conversion of cell •Confers autonomous growth of initiated cell •Irreversible
  14. 14. THEORIES AND RESEARCH MODELS OF TUMORDEVELOPMENTKey Points of Major of TumorgenesisTheory Key PointsMutagenic Mutagenesisversus •Results in qualitative or quantitative alteration informationepigenetic •Chronic insults produce two to three mutations in individual cells within particular tissues •These mutations initiate tumors Epigenetic process •Chronic insults repeatedly injure and transiently excite many cells in particular tissues •These insults alter expression of genetic information at the transcriptional, translational, or posttranslational levels •Mutations are secondary events
  15. 15. THEORIES AND RESEARCH MODELS OF TUMORDEVELOPMENTKey Points of Major of TumorgenesisTheory Key PointsNature versus Mutagens found in the environment (nurture) must interact withnurture DNA (germ or somatic cell) to induce mutations un genes affecting cancer progress directly (e.g., oncogenes/tumor suppressor genes) or indirectly (e.g., DNA repair genes, growth factors)Oncogene and Oncogenes: Do not contact inhibit; do not terminally differentiatetumor or undergo apoptosissuppressor Tumor suppressor genes: When mutated, do not stop unregulatedgene cell growth, induce differentiate, or undergo apoptosis Stem cellStem cell versus •Pluripotent stem cells restricted to allow a finite number of cell tode- only specific lineage of cell types within the organs that arise fromdifferentiation the stem cells •Daughter (progenitor) cells of these pluripotent stem cells would give rise to terminally differentiated cells of that lineage Dedifferentiation: Some progenitor cells could revert back to a pluripotent cell
  16. 16. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsCytological changes Increased size and Reflects greater activity of number of nucleoli tumor cells Increased Larger nucleus reflects nuclear/cytoplasmic ratio more activity, more Altered cytoskeleton genetic information Changes contribute to increased mortality and variable sizes and shapes (pleomorphism) ImmortalityAltered cell growth Normal cells senesce (ramian viable but do not divide) During a crisis, cells mature, proliferate indefinitely, become “immortal”
  17. 17. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsAltered cell growth Immortality Telomeres (DNA segments at the ends of chromosomes) limit the number of cell doublings. Telomeres shorten with each chromosomal replication until reaching a threshold at which cells senesce. Telomere stability is critical for cancer progression. Many cancer cells contain telomerase, an enzyme that prevents telomere shortening and enables the cell to replicate indefinitely
  18. 18. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsAltered cell growth Decreased density- Normal cells stop growing dependent growth when they contact other inhibition (loss of contact cells crowding from inhibition) contact compromises access to nutrients Transformed cells do not respond to physical contact and with chemical signals from neighboring cells, thereby continue to grow beyond normal limits Loss of contact inhibition may result from a faulty restriction point
  19. 19. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsAltered cell growth Decreased requirement Serum normally provides for serum growth factors necessary for cell development and survival Typically, the growth factor binds to a receptor on the cell surface, which in turn activates the intracytoplasmic portion of the receptor to send a message to the nucleus (signal transduction), where an effect on gene function occurs.
  20. 20. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsAltered cell growth Decreased requirement Sometimes, an abnormal for serum growth factor receptor on the surface of cancer or transformed cell can activate the signal pathway spontaneously without exposure to growth factor Cancer and transformed cell lines may grow in media without serum, suggesting that they can synthesize and secrete their own growth factors (autocrine stimulation)
  21. 21. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsAltered cell growth Loss of anchorage- Cells require a substance dependent growth to grow. Transformed cells do not require a solid substrate Only tumor cells grow in soft agar (no anchorage); cell growth in soft agar is highly correlated with tumorigenicity Loss of cell cycle control Cell does not progress normally through cell- cycle pathways and checkpoints Reduced apoptosis Cancer cells are less susceptible to programmed cell death
  22. 22. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsChanges in cell New surface antigens Cancer and transformedmembrane cells exhibit new molecules on the surface Viruses can transform and alter multiple cell- surface antigens New or altered Transformed cells usually glycoproteins (proteins have profound changes in with polysaccharides) cell-surface glycoproteins Some changes may alter cell-cell and cell-matrix adhesions Mechanism by which polysaccharides are made and attached to protiens is deranged in transformed cells
  23. 23. Properties of CancerProperty Characteristics of Cancer Explanation and Transformed CellsChanges in cell New or altered glycolipids Content and complexity ofmembrane glycolipids are reduced in transformed cell membranes Glycosphingolipid interacts with receptor proteins on the surface of normal cells to inhibit their responsiveness to growth factors Transformed cells have less and/or altered glycosphingolipids on their cell surfaces, increasing their responsiveness to growth factors. Glycosphingolipids also serve as components of surface markers involved in normal cell growth
  24. 24. THE CELL CYCLE
  25. 25. THE CELL CYCLE A malfunction of any of these regulators of cell growth and division can result in the rapid proliferation of immature cells In some cases these proliferating immature cells are considered cancerous (malignant) Knowledge of the cell cycle events is used in the development of chemotherapeutic drugs, which are designed to disrupt the cancer cells during different stages of their cell cycle
  26. 26. CARCINOGENESIS Three-step process1. Initiation – initiators (carcinogens), such as chemicals, physical factors, and biologic agents escape normal enzymatic mechanisms and alter the genetic structure of the cellular DNA2. Promotion – repeated exposure to promoting agents causes the expression of abnormal or mutant genetics information3. Progression – the altered cells exhibit increased malignant behavior; they now have the propensity for invasion and metastasis
  27. 27. CARCINOGENESIS Etiologya. Viruses and bacteriab. Physical agentsc. Chemical agentsd. Genetics and familial factorse. Dietary factors – fats, alcohol, salt-cured or smoked meats, nitrate-containing and nitrite containing foods, red and processed meatf. Hormonal agents – DES, OCP and prolonged progesterone therapy
  28. 28. DIETARY FACTORS Alcohol increases the risk of cancers of the mouth, pharynx, larynx, esophagus, liver, colorectum, and breast Greater consumption of vegetables and fruits is associated with decreased risk of lung, esophageal, stomach, and colorectal cancers High caloric dietary intake is also associated with an increased cancer risk Obesity is clearly associated with endometrial cancer, postmenopausal breast cancers, and colon, esophagus, and kidney cancers, as wells as pancreatic cancer, gallbladder, thyroid, ovary, cervix, prostate cancer, and multiple myeloma
  29. 29. GRADING VERSUS STAGING Grading – identification of the type of tissue from which the tumor originated and the degree to which the tumor cells retain the functional and structural characteristics of the tissue of origin Staging – process of determining the extent of disease, including tumor size and spread or metastasis to distant sites TNM StagingT – primary tumorN – regional nodal metastasisM – distant metastasis
  30. 30. TNM CLASSIFICATION SYSTEM Primary tumorTx – Primary tumor cannot be assessedT0 – No evidence of primary tumorTis – carcinoma in-situT1, T2, T3, T4 – increasing size and/or local extent of the primary tumor Regional lymph node metastasisNx – Regional LN cannot be assessedN0 – No regional LN metastasisN1, N2, N3 – Increasing involvement of regional LN Distant metastasisMx – Distant metastases cannot be assessedMo – No distant metastasesM1 – Distant metastases
  31. 31. CANCER WARNING SIGNS AND SYMPTOMS C change in bowel habits sign of colorectal cancer A sore that does not heal on the skin or in the mouth could be malignant Unusual bleeding or discharge from rectum, bladder or vagina could be colorectal, prostate, bladder or cervical cancer Thickening of breast tissue or a new lump in breast Indigestion or trouble swallowing cancer of the mouth throat esophagus or stomach. Obvious changes to moles or warts could be skin cancer Nagging cough or hoarseness that persists for four to six weeks could be cancer of lung or throat cancer.
  32. 32. OTHER MANIFESTATIONS OF CANCER Impaired immunity Hemorrhage Anemia Anorexia-cachexia syndrome Paraneoplastic syndromes – indirect effects of cancera. Breast, ovarian, and renal cancers may set up ectopic parathyroid hormone sites, causing severe hypercalcemiab. Oat cell and lung cancers may produce ectopic secretions of insulin, PTH, ADH, and ACTH Pain
  33. 33. OTHER MANIFESTATIONS OF CANCER Physical stress – when the immune system discovers a neoplasm, it tries to destroy it using the resources of the body Psychologic stress
  34. 34. ROLE OF THE NURSE caregiver advocate case manager educator change agent counselor educator epidemiologist