Pathophysiology Cancer

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Control of Cellular Growth

- Protein growth factors
- Genes, which themselves code for:
- growth factors
- growth factor receptors
- proteins involved in cell adhesion and communication

Stem Cell Differentiation

- Stem Cell: multipotential cell
- Daughter Cell: limited potential cell
- Differentiated cell: end stage of differentiation

Neoplasia

New and abnormal development of cells that may be benign or malignant

Benign

cells that do not invade the surrounding tissue

Malignant

grow by invading surrounding tissue and have the ability to travel and proliferate at distant sites

Anaplasia

change in the structure, function or orientation of cells compared to the parent cell

Cancer

a neoplasm characterized by the uncontrolled growth of anaplastic cells

Autonomy

the cancer cell has become independent from normal cellular controls
- signal transduction
- cell cycle control is lost
- DNA repair is not maintained
- cell growth is abnormal
- differentiation decreases
- apoptosis ceases
- growth factors don't function
- growth factor receptors are lost

Dysplasia

characterized by abnormal cellular changes in
- size
- shape
- appearance
progresses to neoplasia

Proto-oncogenes

unaltered, normal allele of gene that controls cellular growth and differentiation

Oncogene

- potentially cancer causing gene
- proto-oncogene that has been altered (mutated) by a carcinogenic agent

Anti-oncogenes (tumor suppressor gene)

encode for genes that inhibit cell division

carcinomas

epithelial tissue
- squamous cell _____________

sarcomas

connective tissue
- osteo___________

lymphomas

lymphatic tissue
- lymphoblastoma

adenoma

glandular tissue
- adinocarcinoma

fibroma

benign

chondroma

benign

osteoma

benign

lipoma

benign

hemangioma

benign

papilloma

benign

fibrosarcoma

malignant

chondrosarcoma

malignant

osteosarcoma

malignant

liposarcoma

malignant

hemangiosarcoma

malignant

retinoblastoma

malignant

Systemic Effects of Neoplasms

- vessel invasion (bleeding)
- lymphatic invasion (lymphadema)
- nerve invasion (pain, numbness, tingling)
- bone invasion (pain and fractures)
- bone marrow invasion (pancytopenia, infection, bleeding)
- liver invasion (hepatic insufficiency)

Loss or modification of glycoproteins and/or glycolipids

- decreases the transformed cell's response to growth factors
- decreased intercellular communication
- may stimulate an immune response

Fibronectin

- cell surface and transmembranous glycoprotein
- like elastin and collagen, it is an anchoring molecule
- also contributes to the formation of the cytoskeleton

Low Fibronectin can cause changes in:

- cellular organization and structure
- cell-to-cell contact and adhesion
- cell migration or location stability

True or False: Cancer pts have high serum levels of fibronectin

True

True or False: Cancer cells can make defective fibronectin

True

Increased collagenase and other proteolytic enzymes

- Enzyme secreted by cancerous cells that break down barriers, such as basement membranes and other connective tissue barriers
- Increased lytic enzymes cause extracellular proteolysis which contributes to cancer cell invasion.
- carcinoma and sarcoma invasion through basement membranes

Fewer or altered anchoring junctions and gap junctions between cells

- Anchoring junctions connect the cytoskeleton of a cell with another cell or extracellular matrix
- without anchoring, cells are allowed to metastasize, or grow in new environments
- Gap junctions ar small channels between cells that allow ions and soluble molecules to move between cells.
- the more metastatic a tumor becomes, the greater the loss of intercellular communication

Tumor Cell Markers

substances produced by cancer cells that are found on cancer cell membranes in the blood, CSF, or urine

Tumor Cell Markers

- screen and identify individuals at high risk for cancer
- dx specific types of tumors
- observe clinical course of cancer
- often lack specificity, sensitivity, predictability, and feasibility, so there is not an ideal one

Hormones

- tumor cell marker
- ACTH, insulin, HCG, parathyroid, etc
- "ectopic" __________ production is the production of ______________ by tumors of non-endocrine origin.

Enzymes

- tumor cell marker
- usually only detected in the blood when the tumor is very large or metastases has occured

Genes

- tumor cell marker
- genetic marker with the cells (genes and oncogenes)
- Philadelphia Chromosome: translocation between chromosomes 9 & 22

Antigens

- tumor cell marker
- cancer cells express "non-self" ___________

Antibodies

- tumor cell marker
- produced by some cancers (multiple myeloma)
- used to detect specific tumor markers
- also produced by researchers to target specific tumor antigens for the immune system

Age increases the incidence of cancer through the accumulation of:

- environmental agents/carcinogens or their effects
- retroviral insertion of genetic material (reverse transcriptase)
- tumor-suppressor gene inactivation from multiple factors

The development of cancer usually involves

- the loss of the cell's ability to terminally differentiate
- a loss of the cell's ability to control growth
- an increase in the diseases' ability to migrate and invade other tissues

Initiation

the irreversible developmental stage of a cancer precursor cell after the exposure to a carcinogenic agent

Promotion

the exposure of a precursor cell to promoting agent to produce an autonomous phenotype

Progression

depends on structural changes in the chromosome

Carcinogenic Risk Factors

- tobacco use
- diet
- immune system competency/deficiency
- sexual/reproductive behavior
- air pollution, occupational hazards, radiation

Chemical Carcinogens

- cigarettes (lung, bladder, pancreas)
- alcohol (breast and colorectal)
- cigarette/alcohol combo increases a person's risk for oral, throat, and liver cancers
- xenobiotics: toxic, mutagenic, and carcinogenic chemicals in food
- high fat diet, preservatives (nitrates)
- asbestos, dyes, rubber, paint, etc.

Ultraviolet Light (UV)

- carcinogen for basal cell and squamous cell carcinomas
- causes changes in tumor suppressor genes

Ionizing Radiation

- causes DNA alterations and chromosome abberations
- release free radicals

Oncogenic Viruses

alter the genetic makeup of the cell, which alters the daughter cells of the host cell
- direct insertion of DNA into host cell
- synthesis of DNA from RNA using the enzyme reverse transcriptase (HIV)
- cessation of protein synthesis

Epstein Barr Virus

inherited immunodeficiency, lymphoma, Burkitt's lymphoma (cancer of B lymphocytes)

Papilloma Virus

Cervical cancer

HIV

Kaposi's sarcoma

Hep B

Liver Cancer

Helibacter pylori

common cause of peptic ulcer disease, gastric lymphomas, and carcinomas

Tumor-Specific Antigens (TSA)

the "non-self" antigens on the surface of cancer cells
- B cells defend against cancer by producing __________ antibodies
- Macrophages, neutrophils, and T-killer cells can participate in destroying cancerous cells

Viral Antigens (TSA)

produced expressed by virally transformed cells (Burkitts Lymphoma)

Oncofetal Antigens (TSA)

expressed by cells during embryonic development but are absent or low in normal adult cells
- alpha-fetoprotein in hepatic, pancreatic, and epithelial tumors
- carcinoebryonic antigen (CEA) in colonic, pancreatic, and breast tumors

Oncogene products (TSA)

- Proteins associated with cellular growth and differentiation
- Lung Cancers

Carbohydrate TSA

- Transiently expressed in normal tissues during development
- Re-expressed in neoplasms
- Expressed in melanomas

Protein TSA

- Function in proliferation, enzymatic processes, receptors, and cellular structures
- Prostate specific antigen

Tumors escape the immune system by:

- Antigenic modulation and antigen masking (antigen covered up, shed, or taken inside the cell)
- Secretion of immunosuppressive substances (prostaglandin E secretion to block lymphocyte proliferation)
- Escape or sneaking through (initial cancerous cells look very similar to the original normal cells)

Tumors escape the immune system by:

- Blocking factor (antibodies bind to the TSA but don't activate the immune system)
- Immunostimulation (the presence of a low to moderate number of T cytotoxic cells can cause increased tumor growth)
- TSA-reactive suppressor T lymphocytes (to keep the immune system under control, there is a suppressive feature)

Invasion - Cellular Multiplication

- increase rate of multiplication
- increased number of cells dividing
- number of cells lost

Invasion - Mechanical Invasion

Growth of neoplasms, builds up pressure in surrounding tissues and cuts off the blood supply to the local tissue. This decreases the initial resistance to growth and aids the spread of the neoplasm

Invasion - Lytic Enzymes

- Degrading surrounding tissue decreases the resistance to neoplasm growth
- Malignant tumors produce and secrete _____ __________; they also encourage infiltrating macrophages to also release their contents
- Protease
- Type IV collagenase
- plasminogen activators

Invasion - Decreased Cell Adhesion

- cancer cells have less adhesive properties than normal cells
- cancer cells have defective fibronectin or break it down as it is produced
- lack of fibronectin allows cancer cells to slip between cells and increase invasion

Invasion - Increased Motility

- Cancer cells detach from the primary tumor and infiltrate adjacent tissue (intravasation) and vessel walls
- Cancer cells contain growth and motility factors that assist them with systemic motility
- Autocrine motility factors (cancer cells secrete their own motility factors)

Three Step Theory of Invasion
Tumor Cell Attachment

- Mediated by fibronectin and laminin
- Laminin is a glycoprotein that makes up a major portion of basement membranes
- Binding occurs between tumor cell laminin receptors and the basement membranes

Three Step Theory of Invasion
Degradation of the Matrix

- Tissue compartments are separated from each other by two types of matrix: basement membranes and connective tissue (main constituents: collagens, glycoproteins, and proteoglycans)
- Tumor secretes lytic enzymes or encourages host cells to secrete their contents to destroy the matrix

Three Step Theory of Invasion
Locomotion into the Matrix

- Finger-like projections (pseudopodia) extend from the tumor cell and attach to the basement membrane within blood vessel walls
- The cancer cells will then leave the vasculature and enter the interstitial stroma
- Locomotion is directed by chemotactic factors

Three Routes of Metastatic Spread

1. Direct or continuous extension
2. Lymphatic Spread
3. Bloodstream (hematogenous) Dissemination

Direct Tumor Extension

- Loss of cellular adhesion
- Cells move through tissue barriers

Lymphatic Metastasis

- lymphatic routes occur near the edges of the tumor and offer little resistance
- tumor cells entering the lymphatic vessels are carried to nearby lymph nodes. Once there, the body may prevent the spread of the cells or the cells can remain dormant in the lymphatic system
- if cells pass into efferent vessels, metastasis of the lymphatics can occur

Hematogenous Metastasis

Tumor cells penetrate blood vessels, break loose, and are disseminated via the circulatory system.
- Cells must:
- escape host defenses
- survive mechanical trauma of the bloodstream
- lodge in the vascular supply of a target organ and invade the parenchymal cells

Angiogenesis

- growth of cancer cells beyond a few mm requires the development of an adequate new blood supply
- growth of new vessels involves a cascade similar to the coagulation cascade
- this vessel network develops as a result of substances secreted by the tumor (Increase in growth factors and decrease in vessel growing inhibitors)

p53 gene

-codes for a protein that inhibits cells growth and mitosis in cells with damaged DNA
- keeps cell growth and proliferation under control
- if mutations occur, the mutated cells loose their "emergency brake" and are allowed to grow without control
- with the loss of the _______ protein, cell with damaged DNA can undergo uncontrolled reproduction, overwhelming the body's defense mechanisms.

Organ Tropism

Although many potential sites for metastasis sites can be invaded by malignant celss, certain types of cancerous cells have preference for specific organs

Factors Encouraging Organ Tropism

- Growth Factors
- Hormones
- Adherence of tumor receptors
- Chemotactic Factors
- Genetics

Stage 1

Neoplastic cells in original site
well differentiated cells

Stage 2

Metastatic cell in original site and local lymphatics
moderately differentiated cells

Stage 3

Cells in original site and distant lymphatics
poorly differentiated cells

Stage 4

metastatic cells are found in many body areas
very poorly differentiated cells

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