PathoPhysiology Chapter 7

transcript

Chapter 7

Neoplasia

NEOPLASIA• Means “new growth”• Implies abnormality of cellular

growth/tumor• Malignant neoplasm is cancer• Benign growth is generally easily cured• Malignant cancer may not be survivable• Cancer is associated with altered

expression of cellular genes

Neoplasia

BENIGN VS. MALIGNANT GROWTH

Malignant Tumor• Can kill host if untreated• Confirmed by invasive or metastasizing

nature• Tissue-specific differentiation (does not

closely resemble tissue type of origin)• Greater degree of anaplasia indicates aggressive

malignancy• Grows rapidly, may initiate tumor vessel

growth, frequently necrotic, dysfunctional

BENIGN VS. MALIGNANT GROWTH (CONT.)

Benign Tumor• Does not have potential to kill host, but

may be life-threatening because of its location

• Does not invade adjacent tissue or spread to distant sites

• Many are encapsulated• More closely resembles original tissue type• Grows more slowly, little vascularity, rarely

necrotic, often retains original function

BENIGN VS. MALIGNANT GROWTH (CONT.)

Benign Tumor• “-oma” suffix indicates benign tumor

(adenoma)• “-carcinoma,” “-sarcoma” indicate

malignant tumors• Carcinoma: malignant tumor of epithelial

origin (adenocarcinoma)• Sarcoma: malignant tumor of mesenchymal

origin• Leukemia: malignant growth of white blood

EPIDEMIOLOGY AND CANCER RISK FACTORS

• Cancer is 2nd leading cause of death in the U.S.

• Most cancer deaths occur in individuals over age 55

• Men have 1:2 risk of developing cancer; women have 1:3 risk

• 5-year survival rate: 66%

EPIDEMIOLOGY AND CANCER RISK FACTORS (CONT.)

• One third of cancer-related deaths may be attributable to lifestyle factors• Tobacco use• Nutrition• Obesity• Sun exposure (skin cancer)• Sexual exposure to HPV (cervical cancer)

• Early screening aids in early detection

TOBACCO USE• Death rate from lung cancer has

dramatically increased (may be directly related to smoking)

• Lung cancer: leading cause of death in men and women; worst survival rate

• Also linked to pancreatic, kidney, bladder, mouth, esophageal, and cervical cancers

TOBACCO USE (CONT.)

TOBACCO USE (CONT.)• Two types of carcinogens

• Initiator (causes genetic damage)• Promoter (promotes tumor growth)

• Tobacco smoke contains both types• Second-hand smoke also increases risk for

lung cancer

TOBACCO USE (CONT.)

NUTRITION• Dietary factors believed to be related to

cancer risk• Fat• Fiber• Alcohol• Antioxidants

GENETIC MECHANISMS OF CANCER

• Carcinogen• Potential cancer-causing agent

• Proto-oncogene• Overactivity of cancer-critical genes contributes to

cancer• Oncogene

• Proto-oncogene in its mutant overexpressed form• Tumor suppressor gene

• Too little gene activity; inhibits cell proliferation• Cancers may arise when tumor suppressor gene

function is lost or abnormally inhibited

PROTO-ONCOGENES• Normal cellular genes that can be

transformed into oncogenes by activating (gain-of-function) mutations

• Code for• Growth factors• Receptors• Cytoplasmic signaling molecules• Nuclear transcription factors

PROTO-ONCOGENES (CONT.)

GROWTH FACTORS (MITOGENS)Small Cell−Manufactured Peptides • Secrete into extracellular space• Diffuse to nearby cells• Interact with receptors on target cell

surface• Activate signaling cascade; can produce

autocrine signaling

GROWTH FACTOR RECEPTORS• Transmembrane proteins

• Mitogen-binding area on outside of cell• Enzyme-activating area on inside of cell

• Will bind with only one particular mitogen• Binding activates cell proliferation

CYTOPLASMIC SIGNALING PATHWAYS

• Involve numerous enzymes and chemicals that normally function to transmit signals from activated receptors at cell surface to cell nucleus

• Mutant proto-oncogene can activate pathway, even when no signal received at cell surface

TRANSCRIPTION FACTORS• Proteins that must be assembled at the

promoter area to begin gene transcription• Normally sequestered and prevented from

indiscriminate activity until appropriate signals cause their release

• Mutations may cause overproduction of transcription factors

FROM PROTO-ONCOGENE TO ONCOGENE

• Proto-oncogenes become activated oncogenes when mutations alter their activity so that proliferation-promoting signals are generated inappropriately• Oncogenes introduced to host cell by

retrovirus• Proto-oncogene within cell suffers a

mutagenic event• DNA sequence may be lost/damaged and

allows proto-oncogene to become abnormally active

• Error in chromosome replication causes extra copies of proto-oncogene in the genome

FROM PROTO-ONCOGENE TO ONCOGENE (CONT.)

• Retrovirus • HIV

• Kaposi’s sarcoma• Epstein-Barr virus

• Burkitt lymphoma• Human T-lymphocyte virus type 1

• Adult T-cell leukemia/lymphoma• Composed of RNA • Contains reverse transcriptase enzyme

• Directs synthesis of a DNA copy of viral RNA

FROM PROTO-ONCOGENE TO ONCOGENE TRANSCRIPTION

FACTORS

TUMOR-SUPPRESSOR GENES• Contribute to cancer only when not present• Both copies of tumor suppressor genes are

inactivated when cancer develops• One can inherit a defective copy of tumor

suppressor gene from 1 or both parents

TUMOR-SUPPRESSOR GENES (CONT.)

RB GENE• Codes for large protein in cell nucleus

(pRb) that is the “master break” for the cell cycle

• Blocks cell division• Binding transcription factors• Inhibits T factors from transcribing genes that

initiate cell cycle• Can be induced to release transcription

factors when sufficiently phosphorylated• An inactivating mutation of the Rb gene

removes 1 major restraint on cell division

RB GENE (CONT.)

P53 GENE• Most common tumor-suppressor gene

defect identified in cancer cells• More than ½ of all types of human tumors lack

functional p53• Inhibits cell cycling• Accumulates only after cellular (DNA)

damage• Binds to damaged DNA and stalls division

P53 GENE (CONT.)

P53 GENE (CONT.)• May direct cell to initiate apoptosis• Allows genetically damaged/unstable cells

to survive and continue to replicate• Chemotherapy/radiation

• Damages target cell to trigger p53-mediated cell death

• Cancer cells that lack functional p53 may be resistant to chemotherapy/radiation

BRCA1 AND BRCA2 GENES• Breast cancer genes• Family history and inherited defect in

BRCA1 increases risk of breast and ovarian cancer

BRCA1 AND BRCA2 GENES (CONT.)

MULTISTEP NATURE OF CARCINOGENESIS

• Initiation• Promotion• Progression

MULTISTEP NATURE OF CARCINOGENESIS (CONT.)

INITIATION• Initiating events

• Genetic mutations• Inappropriately activate proto-oncogenes• Inactivate tumor suppressor genes

• Proliferation• Required for cancer development (nonproliferating

cells cannot cause cancer)• Each type of cancer has its own

combination of mutations that lead to malignancy

INITIATION (CONT.)

INITIATION (CONT.)• Complete carcinogens

• Capable of initiating cell damage as well as promoting cellular proliferation

• Partial carcinogens• Promoters that stimulate growth• Incapable of causing genetic mutations sufficient

to singly initiate cancer

PROMOTION• Stage during which mutant cell proliferates

• Activation of another oncogene• Inactivation of tumor suppressor gene• Nutritional factors• Infection

• Regulated by many hormonal growth factors (hormones may be promoters for certain cancers)• Estrogen• Testosterone

PROGRESSION• Mutant, proliferating cells begin to exhibit

malignant behavior• Malignant cells commonly produce

telomerase (an enzyme that repairs telomeres and may be a key for attaining immortality)

• Cells whose phenotype gives them a growth advantage proliferate more readily

• Requires multiple steps

PROGRESSION (CONT.)

METASTASIS• Process by which cancer cells escape their

tissue of origin and initiate new colonies of cancer in distant sites• Specialized enzymes and receptors enable them

to escape their tissue of origin and metastasize

METASTASIS (CONT.)

PATTERNS OF SPREAD• Cancer cells generally spread via circulatory

or lymphatic systems• Tumor markers help identify parent tissue of

cancer origin• Rely on some retention of parent tumor

characteristics• Some released into circulation• Others identified through biopsy• Enzymes typically used as tumor markers• Help track tumor activity

ANGIOGENESIS• Process by which cancer tumor forms new

blood vessels in order to grow• Usually does not develop until late stages of

development• Triggers are not generally understood• Inhibition of angiogenesis is important

therapeutic goal

GRADING AND STAGING OF TUMORS

• To predict clinical behavior of malignant tumor and guide therapeutic management

• Grading• Histologic characterization of tumor cells • Degree of anaplasia• 3 or 4 classes of increasing degrees of malignancy

GRADING AND STAGING OF TUMORS (CONT.)

• Staging• Location and patterns of spread within the host• Tumor size, extent of local growth, lymph node

and organ involvement, distant metastasis• TNM system most widely used• Results of staging determine treatment

modality

GRADING AND STAGING OF TUMORS

EFFECTS OF CANCER ON THE BODY

• Depends on location of tumor and extent of metastasis

• Early stages may be symptomatic• Tumor increases in size and spreads; more

symptoms become apparent

EFFECTS OF CANCER ON THE BODY (CONT.)

WARNING SIGNS OF CANCER• Change in bowel or bladder habits• A sore that does not heal• Unusual bleeding or discharge• Thickening or lump in breast or elsewhere• Indigestion or difficulty swallowing• Obvious change in wart or mole• Nagging cough or hoarseness

WARNING SIGNS OF CANCER IN CHILDREN

• Continued, unexplained weight loss• Headaches with vomiting in the morning• Increased swelling or persistent pain in

bones or joints• Lump or mass in abdomen, neck, or

elsewhere• Development of whitish appearance in pupil

of the eye• Recurrent fevers not caused by infections• Excessive bleeding or bruising• Noticeable paleness or prolonged tiredness

PAIN• Common and feared complication• May be due to metastasis, tissue

destruction/inflammation• May be caused by cancer treatment• Usually controlled with analgesics

CACHEXIA AND IMMUNE SYSTEM DEFICITS

• Cachexia• Overall weight loss and generalized weakness

• Loss of appetite (anorexia)• Increased metabolic rate• Nausea/vomiting

• Immune system suppressed by cancer cell secretions

• Some cancers can elude immune system detection

BONE MARROW SUPPRESSION• Contributes to anemia, leukopenia, and

thrombocytopenia• Due to invasion and destruction of bone

marrow cells, poor nutrition, and chemotherapy

• Anemia: Deficiency in circulating red blood cells

LEUKOPENIA• Deficiency in circulating white blood cells

• Primary cause• Malignant invasion of bone marrow

• Contributing factors• Malnutrition• Chemotherapy

• Opportunistic organisms can only infect immunocompromised host

• Infections difficult to manage, prevent

THROMBOCYTOPENIA• Deficiency in circulating platelets

• Important mediators in blood clotting• Predispose to life-threatening hemorrhage

• Anemia, leukopenia, thrombocytopenia can all be managed by blood replacement therapy

OTHER EFFECTS• Hair loss and mucositis

• Complications of chemotherapy and radiation therapy• Mucositis primary source of cancer pain and anorexia• May provide a portal for infection

• Paraneoplastic syndromes • Hypercalcemia• Cushing syndrome secondary to ACTH secretion• Hyponatremia and water overload secondary to

excess ADH secretion

CANCER THERAPY• Early detection best prognosis for cure• Mainstays of therapy

• Surgery• Radiation therapy• Chemotherapy• Drug therapy

• Emerging therapies• Immunotherapy• Targeted molecular therapies• Stem cell transplantation

CANCER THERAPY (CONT.)

SURGERY• Majority of patients with solid tumors are

treated surgically• Main benefit: removal of tumor with

minimal damage to other body cells• Lymph nodes biopsied and/or removed• Commonly accompanied by radiation

therapy or chemotherapy

RADIATION THERAPY

• Kills tumor cells by damaging nuclear DNA• Kills cells that are nonresectable due to

location, missed by surgery, or undetected• May not kill cells directly, but initiates

apoptosis• Small doses of radiation over several

treatments (difficult to kill at once because cells on different cycles)

• Some normal cells killed during radiation therapy

DRUG THERAPY• Systemic administration of anticancer

chemicals to treat cancers known or suspected to be disseminated in the body

• Finds cancer cell targets in the body• Most are cytotoxic• Not selective for tumor cells (normal cell

death may also occur)

DRUG THERAPY (CONT.)• Most effective on rapidly dividing cells• Several courses ensure all cancer cells

killed• Serious side effect: bone marrow

suppression

IMMUNOTHERAPY• Primarily involves use of:

• Interferons• Glycoproteins produced by immune cells in response

to viral infection• Interleukins

• Peptides produced and secreted by white blood cells• Monoclonal antibodies

• Antibodies with identical structure that bind with specific target antigens

• Generally used as adjuncts to surgery, irradiation, and chemotherapy

GENE AND MOLECULAR THERAPY

• May have high therapeutic potential• May be used to suppress overactive

oncogenes or replenish missing tumor suppressor function

• Current uses• Genetic alteration of tumor cells to make them

more susceptible to cytotoxic agents or immune recognition

• Genetic alteration of immune cells to make them more efficient killers of tumor cells

• Can be directed at cells other than cancer cells

STEM CELL TRANSPLANTATION• Used to manage life-threatening disorders

in which patient’s bone marrow cannot manufacture white blood cells, red blood cells, or platelets

• Also applied to other malignancies and to nonmalignant disorders

• Provides a method to restore bone marrow function after high-dose irradiation or chemotherapy

PathoPhysiology Chapter 7

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