Patho Ch. 07 - Cell Proliferation & Differentiation

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Cell Proliferation

Generation of new, daughter cells divided from parent cells. Occurs through mitosis, in response to a need. Under control of genes.

Ex - skin cells & RBCs

Goal of Proliferation

To replace cells that have undergone necrosis or apoptosis.

Overproliferation

Crowding of cells that occurs with loss of balance regulation.

Regulated balance

A balance of cell death and growth is needed for homeostasis

What is differentiation? What are the 3 categories.

Maturity, specificity & functionality.

1. Undifferentiated stem cells have the potential to mature into more specific cell types
2. Progenitor cells reproduce daughter cells
3. Highly differentiated cels that don't reproduce

What influences differentiation regulation?

Genes
Growth factors
Nutrients
Stimulation from external envi

What are stem cells?

highly undifferentiated units that have the potential to divide into daughter stem cells which can mature into differentiated cells w/ a specific funciton.

Flexible & adaptable

Ex - blood loss > stem cells differentiate into RBC

What is neoplasia?

Irreversible deviant development of cells that results in an abnormal mass of tissue

T/F: Neoplasms only emerge from parenchymal cells/tissues.

F: they can stem from parenchymal (functional organ cells) or stromal (supportive structure) cells/tissues.

T/F: Neoplasms arise only in cells that are capable of proliferation

True. Labile cells (epithelial, blood) are highly susceptible.

What is cancer?

highly invasive/destructive neoplasms.

What is carcinogenesis?

The origin, promotion or development of cancerous neoplasms.

T/F: At the level of the cell, cancer is genetic

True. Always involves the malfunction of genes that control cell reproduction, growth, differentiation & death.

T/F: Less than 2% of cancers are clearly hereditary

False: less than 5%

T/F: 1% of heritable cancer syndromes are passed along germ line cells.

True. Many follow a Mendelian pattern of inheritance.

T/F: Cancer usually develops through an inherited mutation.

False: usually manifests through genetic mutations after birth. Usually related to harmful environmental exposures that injure cell DNA to alter proliferation/differentiation

What does the initiation-promotion-progression theory underscore?

The idea of cofactors in cancer etiology.

What does the initiating event do?

Causes a mutation in a cell

What is the promoting event?

Expansion of the mutated cell's growth & reproduction.

Ex - chronic inflammation, hormones, chemicals.

What is progression?

Extension of the promotion phase, except now the growth no longer needs a promoter, it's AUTONOMOUS.

What is monoclonal origin?

Most cancers originate from a single mutated cell.

What causes the cell mutations that lead to neoplasia?

Often unknown. Most mutations are spontaneous alterations in DNA replication or repair w/ no apparent trigger.

How many mutated genes are required for creation of a cancerous neoplasm?

5 to several hundred.

What are the 3 categories of genes that can lead to cancer?

1. mutator genes (repair mutated DNA)
2. oncogenes (code proteins that regulation cell growth; alter proliferation/differentiation)
3. tumor suppressor genes (prohibit overproliferation & regulate apoptosis; when mutated = immortality)

What are protooncogenes?

"normal" genes with a vital role in regulating cell function. Precursor genes; when activated, become oncogenes via:
point mutation
translocation
gene amplification

Where is activation of oncogenes seen most commonly?

Spontaneous mutation of somatic cells. If activated in germ line cells, there will usually be a spontaneous abortion.

What causes point mutations?

1. arise spontaneously
2. from environmental exposure (chemicals, UV radiation)

What are 3 common types of cancers that result from translocations?

Leukemias, lymphomas, solid tumors.

What is gene amplification? Where is it implicated?

Accelerating the replication of a gene. Alters the chromosome.

Solid tumors (breast, neuroblastoma)

What are 3 oncogene abbreviations? What indicates its origin/location?

ras
neu
myc

v (virus), c (cell/chromosome)

What are tumor suppressor genes? What happens when they are mutated?

Prohibit overproliferation of cells via apoptosis.

Cell becomes immortal and has unrestricted proliferation

Name 3 common tumor suppressor genes

p53 gene
retinoblastoma (Rb) gene
BCL-2 gene

Whose cells were vital for developing the polio vaccine?

How long has she been dead?

What is the total weight of cells grown from HeLa cells?

Henrietta Lacks

60 years

50 million tons

What is telomerase?

An enzyme that adds length to the telomere, the chromosomal "time clock." Telomeres usually shorten as chromosomes age; once the cap falls off, the cell undergoes apoptosis.

T/F: mutator genes, oncogenes, tumor supressor genes & telomerase are sufficient to impair cell function & allow unregulated cell growth

False: they're necessary, but not sufficeint.

Mutated genes are usually just tumor initiators/promotors.

What is a carcingen? What are the 2 categories?

a known cancer-causing agent. Interfere w/ molecular pathways and can initiate/promote tumors.

1. direct - modify cell DNA
2. indirect - induce immunosuppression or chronic inflammation

ex - radiation, free radicals, hormones, tobacco, infectious microorganisms, chemicals

T/F: radiation is both a cause and treatment for cancer

True

What types of radiation can damage or kill the cell?

high-energy ionizing radiation: gamma rays, x-rays, UV rays.

Which cells are most commonly affected by radiation exposure?

Labile cells. Radiation is aimed at cells that are highly proliferative.

T/F: hormones can be used to treat cancer

True. They can also cause cancer.

What are some types of tumors have receptors that are responsive to hormone levels?

Breast, uterus & prostate tumors

How are adrenal corticosteroid hormones (prednisone) used to treat cancer?

They can directly kill tumor cells, esp lymph cells, & inhibit mitosis. Also have anti-inflammatory effects.

What drug is commonly used in breast cancer treatment? What does it do?

Tamoxifen. It blocks the action of estrogen & inhibits tumor growth in breast tissues.

What types of cancer are correlated w/ tobacco use?

Laryngeal, lip, esophageal & bladder.

What percent of cancers are viral infections responsible for?

15%

Ex - hepatitis & HPV

Few bacteria, by contrast, are carcinogenic (H. pylori is an exception)

T/F: Chemical carcinogenesis is heavily influenced by gender.

F: it's influenced by individual susceptibility, lifestyle factors & environment.

3 examples of chemical carcinogens

Asbestos
Benzene
Formaldehyde

What is autonomy?

Unregulated cell growth of neoplasms

What is anaplasia?

describes the neoplasm's loss of differentiation

greater anaplasia > less differentiation > more aggressive tumor

Cytologic analysis will reveal the presence of cells that vary in size & shape w/ enlarged nuclei & rapid, atypical mitosis.

What are the characteristics of cancer (neoplastic) cells?

1. Autonomy
2. Anaplasia
3. Lack cell-to-cell inhibitions (proliferating cells are usually sensitive to presence of neighbors; in wound healing cell-to-cell contact usually stops proliferation; when contact is lost that usually triggers new cell synthesis)
4. Lack cohesions & adhesiveness (easily move between other cells to begin growing in distant sites)

T/F: neoplastic cells secrete substances that can alter metabolic processes.

True

T/F: neoplastic cells are energy independent and undergo extensive angiogenesis.

F: they are energy dependent. They do undergo extensive angiogenesis.

T/F: Neoplasms exhibit normal growth factors for reproduction & angiogenesis.

F: they have deviant & excessive growth factors to allow rapid reproduction/angiogenesis to meet extreme nutrient demands.

How do tumor cells move into neighboring tissues?

They secrete enzymes that degrade the extracellular matrix.

Picture of 8 characteristics of cancer cells

What are paraneoplastic syndromes?

Hormonal, neurologic, hematologic & chemical disturbances in the body that are NOT directly related to invasion by the primary tumor or mets.

What is one possible manifestation of paraneoplastic syndromes?

Hormone disturbances. Neoplasms can produce & secrete ectopic hormones that aren't under the control of the endocrine system and don't respond to feedback mechanisms. Neoplasms can also secrete substances that mimic hormone function

Ectopic

hormone secretion from a site outside an endocrine gland

What is a second possible manifestation of paraneoplastic syndromes?

Disturbances in neurologic function. The hormones neoplasms secrete can disturb fluid & electrolyte balance > jacked up neurologic functioning.

Tumors can also cause generalized numbness, weakness & loss of neurologic function through:
1. promoting brain hemorrhage
2. promoting infection in the CNS
3. denying neuronal tissues a vascular supply

What do the terms benign & malignant refer to?

Tumor location & appearance related to tissue of origin.

What are the characteristics of a benign tumor?

It remains localized & closely resembles the tissue of origin. They overproliferate, but don't have a loss of differentiation.

Volcy slide:
1. slow growth
2. expansion
3. localized
4. well differentiated

T/F: Benign tumors are harmless.

F: large benign tumors can impinge nearby structures, obstruct vital functions and cause death.

What are the characteristics of a malignant tumor?

Invasive, destructive, spread to other sites, don't resemble tissue of origin.

Volcy slide:
1. rapid growth
2. infiltration
3. mets via blood/lymph channels
4. poor differentiation

How do malignant tumors promote ischemia & necrosis?

They use energy & nutrients needed by unaffected tissues.

What is local spread? What are possible outcomes?

Proliferation of the neoplasm w/in the tissue of origin

Promotes loss of function:
obstruction
hemorrhage
necrosis

What is direct extension?

Tumor cells move into adjacent tissues/organs. A defining characteristic of malignancy.

What is seeding?

A form of direct extension in which neoplastic proliferation occurs within peritoneal & pleural cavities surrounding the affected tissue/organ.

What is metastasis?

When neoplasms spread to distant sites via lymph/blood vessels. The lethal aspect of cancer.

What are the 4 steps of metastasis?

1. break through basement membrane (if present) & extracellular matrix
2. gain access to & circulate w/in the blood/lymph systems
3. leave blood/lymph & adhere to distant tissues
4. establish nutrient network through angiogenesis

T/F: Tumors have easier access through the arterial system than the venous or lymphatic systems

F: Lymph capillaries & venules are thinner.

What is tropism? What are 3 factors that promote it?

Describes the affinity of a primary tumor to a specific distant site.

1. favorable envi in the new tissue/organ
2. adherence molecule compatibility between neoplasm & new tissue/organ
3. location or the organ in relation to the path of blood flow.

Ex - colon tumors tend to metastasize in the liver.

How are tumors identified?

Based on tissue of origin

What does the suffix "oma" indicate?

Designates a tumor is based on cell or tissue of origin.

Benign = cell/tissue origin + -oma "epithelioma" "adenoma" "teratoma" "osteoma"

Malignant = cell/tissue origin + carcin/sarc + -oma "adenocarcinoma" "chondrosarcoma"

(carcin = epithelial, sarc = connective tissue)

T/F: Lymphoma, melanoma & leukemia are benign neoplasms.

False. They're malignant, despite their nomenclature.

What are 5 carcinogens?

1. radiation
2. hormones
3. tobacco
4. infectious microoganisms (HPV)
5. chemicals (asbestos)

What is carcinoma in situ?

Describes carcinomas confined to the epithelium that haven't yet penetrated the basement membrane. Can remain "in situ" indefinitely.

T/F: Carcinoma in situ tumors are often asymptomatic.

True. If detected 'in situ' there will usually be a favorable prognosis. Unfortunately many tumors aren't detected until then penetrate the basement membrane.

What is staging?

Classifying the extent/spread of the disease from the site of origin.

Refers to:
size (higher # = bigger size)
location
lymph node involvement
spread (higher # = more spread)

Treatment is based on this.

What system is most frequently used to stage tumors?

TMN

tumor size (primary tumor)
node (lymph) involvement
metastases

What is tumor grading?

Differentiates the level of anaplasia depicted by the tumor.

higher tumor grade > more deviance from tissue of origin.

I (well differentiated) - IV (highly undifferentiated)

T/F: tumors graded I or II resemble the tissue of origin in size, shape, structure & mitotic activity

True. It's III/IV that have little resemblance to the tissue of origin.

Cancer prognosis is usually communicated based on a __ year survival rate.

5

What are 6 manifestations of cancer?

1. lymphadenopathy
2. fever
3. anorexia
4. cachexia
5. palpable mass
6. loss of tissue function

What are the general manifestations of cancer related to? (4 things)

1. systemic inflammatory/immune responses
2. increased metabolic rate induced by tumors
3. paraneoplastic syndromes
4. local effects of tumor encroachment on, or obstruction of neighboring tissues/organs

What causes fever in cancer?

Release of pyrogens from cancer cells and other cells active in the inflammatory response.

What causes anorexia in cancer?

Due to chemical mediators circulating (from inflammatory response), and changes in taste receptors that accompany tumor growth.

What is cachexia & what causes it?

Unexplained weight loss & tissue wasting.

Result of early feelings of fullness with eating; release of chemical mediators like tumor necrosis factor that reduce appetite.

What is leukemia?

Malignant neoplasms of the blood & blood-forming organs. Often associated w/ overproliferation & lack of differentiation in white blood cells (can affect other cell types tho).

"white blood"

What does leukemia put in place of bone marrow cells?

Immature, proliferating neoplasms, aka blast cells.

T/F: Non-functioning leukemic blast cells circulate in the vascular system

True.

What are possible causes of leukemia?

Radiation & chemical exposure.

If treated w/ chemo for lymphomas or other cancers, more prone to develop leukemia.

Down syndrome more susceptible.

Genetic predisposition too.

What are the 2 classifications of leukemia?

1. acute - sudden, result in rapid loss of function
2. chronic - gradual in onset, early symptoms vague.

What are the 2 cell types affected by leukemia?

1. lymphocytic leukemia - immature lymphocytes that originate in bone marrow
2. myelogenous leukemia - myeloid stem cells in marrow. Interferes w/ maturation of blood cells, including erythrocytes & platelets.

What is ALL?

Acute lymphocytic leukemia. Most common cancer in kids, but also occurs in adulthood. Immature B & T lymphocytes are the malignant cells.

T/F: ALL is associated w/ alterations in chromosomal number & translocations

True. Each specific alteration has prognostic significance.

What is AML?

Acute myelogenous leukemia. Most prevalent acute form and occurs most commonly in adults.

Immature myeloid cells proliferate in the bone marrow and can't differentiate. Leads to anemia, leukopenia & thrombocytopenia.

What are risk factors for developing AML?

1. Male
2. Smoking
3. previous chemo/radiation tx
4. history of ALL
5. exposure to atomic bomb radiation or benzene
6. history of myelodysplastic syndrome

What 3 factors of ALL & AML are the clinical manifestations related to?

1. immaturity of white blood cells & other cells originating in the marrow
2. crowding of leukemic cells in marrow
3. infiltration of leukemic cells in CNS, lymph nodes, liver & spleen

What are the clinical manifestations of ALL & AML?

1. Increased infections - (immaturity of white blood cells)
2. Anemia, bruising, epistaxis (nose bleeds) - decreased erythrocyte/platelet production due to leukemic crowding in marrow.
3. Bone pain - leukemic crowding
4. Headaches, visual disturbances, nausea, vomiting, seizures & coma - infiltration into CNS
5. Enlargement/tenderness of organs - infiltration into nodes, spleen, liver
6. Weight loss & fever - unexplained

T/F: chronic leukemias are most commonly found in children.

False. Slower in onset & more common in middle/older adults.

What is CLL?

Chronic lymphocytic leukemia. Results in overproliferation of B lymphocytes that are relatively mature but not fully functional. Can't form antibodies as well, so infection is common.

What is CML?

Chronic myelogenous leukemia. Overprolif of myelogenous cells that are relatively mature but not fully functional.

What differentiates chronic leukemias?

They present certain B-cell antigens & other genetic/chromosomal aberrations.

What are lymphomas?

Malignant lymphocytes or lymphoblasts.

Where are lymphomas derived from? What type of neoplasms do they produce?

WBCs (mostly lymphocytes) & lymph tissue.

Solid organ tumors in lymph tissues, and later, in bone marrow. Can also present in spleen & liver.

What is Hodgkin's lymphoma? What is the cause.

Malignancy of lymphoid tissue. There is painless, progressive enlargement of the cervical lymph nodes.

Cause unknown.

What are HL risk factors?

Epstein-Barr virus
Genetic factors
Immunosuppression

What ages have the highest incidence of HL?

10-30 or older than 50

T/F: the childhood form of HL is similar in biology/pathogenesis to the adult-onset form.

True

T/F: the 5 year survival rate for kids w/ HL is 85%

F: 95%

T/F: the mortality rate for adults w/ HL has declined at a greater pace than any other malignancy

True. Due to better radiation/chemo tx.

What 2 cell types are implicated in HL?

1. multinucleated gian cells (macrophages) called Reed-Sternberg cells
2. mononuclear giant cells called Hodgkins's cells

other inflammatory cells like neutrophils, eosinophils, plasma cells, small lymphocytes & fibroblasts.

What is the lineage of the Reed-Sternberg cell?

Follow b-lymphocyte lineage.

What types of cells does HL typically arise in?

B cells that can't synthesize immunoglobulin & are resistant to apoptosis.

Lung, liver, bones, bone marrow.

HL is organ tropic to these sites.

What is the staging for HL?

I - involvement of single lymph node region
IV - involvement of one or more organs outside lymphatic system.

What are the systemic manifestations of HL?

Weight loss
Fever
Drenching night sweats

(if absent, stage is HL A; if present, stage is HLB)

What are the manifestations of HL?

Nontender enlarged lymph node(s) in the neck - firm/rubbery in texture
Low grade fever
Fatigue
Weight loss
Pruritis (severe itching)
Night sweats
Splenomegaly
Hepatomegaly.

What is NHL?

Non-Hodgkin's lymphoma. Encompasses broad range of B & T cell malignancies. Doesn't have the Reed-Sternberg or Hodgkin cells.

Which occurs more frequently, HL or NHL?

NHL

T/F: NHL is more likely to affect unconnected lymph nodes

True

What factors are implicated in the etiology of NHL?

Viruses
Immunodeficiency
Genetics

T/F: both HL and NHL can spread via the lympatic & vascular systems

True

What sites is NHL tropic to?

Liver, spleen, bone marrow.

What is included in the REAL classification system?

Both lymphomas & leukemias, since they both involve immune cell neoplasms.

What are clinical manifestations of NHL?

Painless enlarged chain of lymph nodes
Increased risk of infection
Paraneoplastic syndromes

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