Neoplasia Chapter 7 Lecture (Putthoff) Flashcards
What causes Cancer?
Cancer is a complex group of diseases with many possible causes: genetics, tobacco, diet and physical activity, sun and UV exposure, radiation exposure and cancer, other carcinogens
How are different cancers alike?
In all cancers, cells grow out of control and spread into surrounding tissues
Cancer is a genetic disease? Does this mean it is inherited?
No, it means it is caused by changes to genes that control the way our cells function, especially how they grow and divide; acquired mutations over time, not necessarily inherited!
What is another cause of lung cancer that is not related to smoking? Which population is this type of lung cancer seen in?
Peripheral scar carcinoma also leads to lung cancer. Usually seen in older women. NOT caused by smoking!
How did cancer get its name?
Cancer usually has a spiculated, undefined border that looks like crab legs and “cancer” is crab in latin
Generic term for all malignant neoplasms?
Cancer
“new growth or form;” results from genetic alterations that are passed down to progeny of tumor cells. These genetic changes allow excessive and unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli); occurs in a spectrum from benign to malignant
Neoplasia
_____ (swelling) was first used as one of the characteristics of acute inflammation. Now frequently used by physicians as a synonym for neoplasia
Tumor
Study of tumors (neoplasms); can be classified into medical, surgical, pediatric, etc
oncology
What is the term used to describe the fact that the entire population of a neoplasm arises from a single cell that has incurred genetic change
clonal
all neoplastic cells are clones of the original altered cell
Do cancers arise from de-differentiation of adult cells?
No! Adult cells do NOT go through metaplastic transformation; only primitive cells do! (aka basal cells?)
____ tumors are designated y attached the suffix -oma
benign
benign epithelial neoplasm derived from glands, although they may or may not form glandular structures
adenoma
benign epithelial neoplasms producing microscopically or macroscopically visible finger like or warty projections from epithelial surfaces
papillomas
Benign epithelial neoplasms that from cystic masses such as in the ovary? cystic masses and fibrous tissue?
cystadenoma
cystadenofibroma
A neoplasms is termed _____ when it can invade and destroy adjacent structures and spread to distant sites (metastasis) to cause death
malignant
Most types of cancers (85%) are ____
carcinomas, most are squamous cell carcinomas
Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers are called _____
carcinomas
i.e, cancers from ectodermally derived epidermis, mesodermally derived renal tubules and endodermally derived lining of GI tract
Cancer in which tumor cells resemble stratified squamous epithelium
sqamous cell carcinoma (most common type)
Lesion in which the neoplastic epithelial cells grow in a glandular pattern.
adenocarcinoma
sometimes tissue or organ of origin can be identified and is added as descriptor like renal cell adenocarcinoma or bronchogenic sqamous cell carcinoma
cancer composed of cells of unknown tissue origin is designated as _____
undifferentiated malignant tumor
Malignant tumors arising in solid mesenchymal tissues are called _____
sarcomas
malignant tumors arising from blood forming cells are called ____
leukemias (white blood) or lymphomas (tumors of lymphocytes/precursors)
divergent differentiation of single neoplastic clone creates a ______
mixed tumor (like mixed tumor of salivary gland)
What things are found within a mixed tumor?
epithelial components scattered within a myxoid stroma that may contain islands of cartlage or bone.
In a mixed tumor, elements arise from a single clone capable of producing both epithelial and myoepithelial cells. This is called ______
pleiomorphic adenoma
Most mixed tumors are composed of cells from a single germ layer except what kind of mixed tumor?
teratoma
____ containns recognizable mature or immature cells or tissues belonging to more than one germ layer (sometimes all 3) because they arise from totipotential germ cells in ovary/testis
teratoma
Neoplasm which differentiates prinicpally along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous gland, and tooth structures
ovarian cystic teratoma (dermoid cyst)
Are teratomas and mixed tumors malignant or benign?
Mixed tumors are rarely malignant, teratomas also are benign
What are the two general components of tissue present in BOTH malignant AND benign neoplams?
Parenchyma and stroma
*classification of tumors based on parenchymal component but growth and spread dependent on stroma
_____ gives rise to neoplastic cellular component, is benign, malignant or other
parenchyma
___ is the supportive cellular component (tissue skeleton upon which the parenchymal component resides); generally not neoplastic (in carcinomals) and typically consists of connective tissue (supporting framework) and blood vessels (nutrition)
stroma
Does the stroma contain malignant cells?
No but may lead to thickness called desmoblastic reaction/desmoplasia??
*some desmoplastic tumors like in female breast are stony hard called scirrhous
polyp vs. adenoma in GI tract
When a neoplasm in the GI tract (benign or malignant) produces a macroscopically visible projection above a mucosal surface and projects into gastric or colonic lumen, it is called polyp; if it has glandular tissue it is called adenomatous polyp
Extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally
differentiation
- 2 major determinants of differentiation are:
1. neoplastic cells nuclei and cytoplasm and 2. architectural relationship of the neoplastic cells and non-neoplastic stroma
lack of differentiation is called _____ and is a hallmark of malignancy; means to form backward, implying a reversal of differntiation to a more primitive level
anaplasia
*The less differentiated a malignant neoplasm, the more aggressive its biologic behavior
Why are benign tumors generally considered well differentiated?
Because they closely resemble the normal cell type and mitoses are usually rare and are of normal configuration
example: neoplastic cells in a lipoma closely resemble normal adipocytes that makes it difficult to recognize the tumor by microscopic exam of individual cells; also leiomyoma of uterus resembles normal smooth muscle cells of myometrium; thyroid adenoma
While malignant neoplasms exhibit wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature. Exception?
Thyroid anemocarcinoma—form normal appearing follicles
some squamous cell carcinomas contain cells that appear identical to normal squamous epithelial cells
Grades of differentiation and clinical relevance?
Grade preceds second word in the phrase differentiated
- well differentiated: closely resembles parent tissue–thyroid carcinoma and some squamous cell carcinoma (like of the skin)
- moderately well differentiated: features of the original tissue type identifiable but not the dominant pattern, with additional atypia
- poorly differentiated: small minority of cellular constituents allow identification of the parent tissue; cellular anaplasia
- undifferentiated: tissue of origin cannot be discerned by histopathologic appearance of neoplasm; always associated with anaplasia
Morphological changes associated with anaplasia
Pleomorphism (different sized cells), abnormal nuclear morphology (nucleus to cytoplasm ratio increases–big nucleus), mitoses, loss of polarity (disorganized growth), other changes (ischemic necrosis)
Difference between metaplasia and dysplasia
metaplasia is replacment of one type of cell with another type; dysplasia literally means disordered growth
Evolution of dysplasia in sqamous epithelium (difference between CIS and carcinoma)
When dysplastic changes are marked and involve the full thickness of the epithelium but the lesion does NOT penetrate the basement membrane its called carcinoma in situ but once the tumor cells breach the basement membrane its is called an invasive tumor (carcinoma)
Does sqamous metaplasia begin in basilar cells or adult cells?
BASILAR CELLS!! Never from adult cells!
Differention in squamous cell carcinoma:
- Well differentiated tumor cells have prominent ____ production and ____ present
- Moderately differentiated has a much more ___ architecture
- Poorly differentiated has keratin present but what?
- keratin, intercellular bridges
- distorted
- keratin ONLY detected with special techniques
What kind of tumors (malignant or benign) retain the functions of the original cells of origin and which tumors sometimes acquire unexpected functions?
Benign retain function, malignant acquire unexpected functions due to derangements in differentiation
_____ tumors are slow growing; ____ tumors generally grow faster
benign, malignant
_____ tumors are poorly circumscribed and invade surrounding normal tissue; ___ tumors are circumscribed and may have a capsule
malignant, benign
Tumors of mesenchymal origin:
One parenchymal cell type
Benign: fibroma and lipoma
Malignant: fibrosarcoma and liposarcoma
Tumors of connective tissue and derivatives
One parenchymal cell type
Benign: chondroma and osteoma
Malignant: chondrosarcoma and osteoenic sarcoma
Tumors of vessels and surface coverings
One parenchymal cell type
blood vessels=hemangioma (B), angiosarcoma (M)
Lymph vessels=lymphangioma (b), lymphangiosarcoma (m)
mesothelium=benign fibrous tumor, mesothelioma (m)
Brain coverings=meningioma (B), invasive meningioma
tumors of blood cells and related cells
One parenchymal cell type
hematopoetic cells=leukemia (M)
Lymphoid tissue=lymphoma (M)
Tumors of muscle
One parenchymal cell type
smooth muscle: leiomyoma (B), leiomyosarcoma (M)
striated muscle: rhabdomyoma (B), Rhabdomyosarcoma (M)
Tumors of epithelial origin
stratified squamous
sqamous cell papilloma, squamous cell carcinoma
Tumors of epithelial origin
Basal cells of skin or adnexa
Basal cell carcinoma (malignant but never metastizes)
Tumors of epithelial origin
lining of glands or ducts
adenoma, adenocarcinoma
papilloma, papillary carcinomas (thyroid)
cystadenoma, cystadenocarcinoma (ovaries)
Tumors of epithelial origin
respiratory passages
bronchial adenoma, bronchogenic carcinoma
Tumors of epithelial origin
renal epithelium
renal tubular adenoma, renal cell carcinoma
Tumors of epithelial origin
liver cells
hepatic adenoma, hepatocellular carcinoma
Urinary tract epithelium (transitional)
transitional cell papilloma, transitional cell carcinoma
Placental epithelium
hydatidiform mole, choriocarcinoma
testicular epithelium (germ cells)
seminoma (malignant; no benign form)
Tumors of epithelial origin
tumors of malocytes
nevus, malignant melanoma
Mixed tumors–more than one neoplastic cell type but usually derived from ONE germ cell layer
salivary glands: pleomorphic adenoma aka mixed tumor of salivary origin (b), malignant mixed tumor of salivary gland origin (m)
renal anlage–wilms tumor (malignant)
Teratogenous–more than one neoplastic cell type derived from MORE than one germ layer–teratogenous
totipotential cells in gonads or embryonic rests: mature teratoma, dermoid cyst (b); immature teratoma, teratocarcinoma (m)
One unequivocal criterion of malignancy
metastasis–tumor to sites physically discontinuous with primary tumor; by definition benign neoplasms do NOT metastasize
How do cancers spread to discontinous areas?
the invasiveness of cancers permits them to penetrate blood vessels, lymphatics and body cavities providing opportunity for spread. All malignant tumors can metastasize but some do so very infreqently
Metastatic cascade:
- clonal expansion, growth, diversification angiogenesis
- Metastatic subclone
- Adhesion to and invasion of basement membrane
- passage through EC matrix
- Intravasation
- interaction with host lymphoid cells
- tumor cell embolus
- adhesion to basement membrane
- extravasation
- metastatic deposit
- angiogenesis
- growth
Sequence of events in the invasion of epithelial basement membranes by tumor cells
tumor cells detach from each other because of reduced adhesiveness and attract inflammatory cells. Proteases secreted from tumor cells and inflammatory cells degrade the basement membrane. Binding of tumor cells to proteolytically generated binding sites and tumor cell migration follow
Examples of cancers that invade early in their course but rarely metastasize
Gliomas (CNS) and basal cell carcinoma (skin)
Examples of metastatic malignancies of blood forming cells?
Trick question! Leukemias and lymphomas are systemic circulating malignancies so the term metastatic does NOT apply!
Cancers by incidence vs. cancers by diagnosis/death in US
Cancers by incidence: 1. prostate/breast 2. lung 3. colon
Cancers by diagnosis/death: 1. lung 2. prostate/breast 3. colon
Most common cancers in developing world
lung, stomach and liver in men; breat, cervix and lung in women
The incidence of cancer varies with geography, age, race, and genetic background. Cancers are the most common in people of what age? but occurs in adults and children of all ages. The geographic variation is due to what?
most common in adults older than 60
geographic variations due to different environmental exposures
Important environmental factors implicated in carcinogenesis:
infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to environmental carcinogens
what increases the risk of cancer?
reparative proliferations caused by chronic inflammation or tissue injury, certain forms of hyperplasia and immunodeficiency
Interactions between ____ and ___ may be important determinants of cancer risk
environmental factors and genetic factors
Smoking is not only associated with lung cancer but also with what other kind of cancer?
AML
Alcohol abuse is associated with what kind of cancer?
Hepatocellular carcinoma
Why is breast cancer risk in females that inherited BRCA1 and BRCA2 tumor suppressor genes 3x higher for women born after 1940?
Reproductive history changes—now women are having many more menstrual cycles because they are having less pregancies and having children later which means more opportunities for mutations during menstrual cycle
Name the type of cancers associated with the following agents:
- arsenic
- abestos
- benzene
- beryllium
- cadmium
- chromium
- nickel
- radon
- vinyl chloride
- lung carcinoma, skin carcinoma
- lung, esophageal, gastric, colon, mesothelioma
- AML
- Lung carcinoma
- prostate carcinoma
- lung and oropharyngeal carcinoma
- lung carcinoma
- hepatic angiosarcoma
Acquired predisposing conditions that are related to cancer
chronic inflammation
precursor lesions
immunodeficiency states
Cancer is the main cause of death among women aged 40-79 and men aged 60-79. why is the incidence of cancer higher with age?
accumulation of somatic mutations associated with emergence of malignant neoplasms
_____ are the most at risk for accumulating the genetic lesions that lead to carcinogenesis
proliferating cells
Tumors arising in the context of chronic inflammation are usually what kind of cancers?
Carcinomas but also include mesothelioma and several kinds of lymphoma
Immunodeficiency states tend to predispose to what kind of cancers?
Virus-induced cancers
Carcinomas, the most common general category of cancer in adults are extraordinarily RARE in ____
Children
When cancer occurs because of an inherited gene mutation, it is referred to as ______. Examples?
Heriditary cancer
Examples: mutations of BRCA1 and BRCA2 are inherited and substantially increase the risk of breast and ovarian cancer
By the time a tumor comes to clinical attention (1gm or 10^9 cells), it has gone through a minimum of ____ divisions
30
(Likely an underestimation since many cells die via apoptosis and due to Darwinian selection of the fittest for nutrients, etc)
The promiscuous tendency of tumors to become more aggressive over time due to selective pressure is called _______
Tumor progression
As a tumor cell population expands, a progressively ____ percent of tumor cells leave the replicating cellular pool
Higher
What does the tumor evolution of a renal carcinoma tell us?
The mutation constituency tends to vary from the original site and even varies between metastatic sites or locales
One of the most profound selective pressures that cancer cells face is ________
Chemotherapy or radiotherapy
*tumors that recur after therapy are almost always found to be resistant if the same treatment is given again because therapy selects for pre existent subclones that by change have a genotype that allow them to survive
Genomic themes in carcinogenesis:
Non lethal genetic damage
Clinal expansion of single precursor cell
4 classes of regulatory genes affected: growth promoting Porto-oncogenes, growth inhibiting tumor suppressor genes, genes that regulate apoptosis, and DNA repair genes
In epigenetic modifications what determines the lineage commitment and differentiation state of both normal and neoplastic cells?
DNA methylation and histone modification dictates which genes are expressed which in turn determines the lineage and differentiation
Cell and molecular hallmarks of cancer
Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Altered cellular metabolism Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize Ability to evade host immune response
Genomic instability and cancer promoting inflammation tend to ____ the features or hallmarks of cancer
Accelerate
All cancers ultimately contain certain cells that are ____ and often exhibit other features related to neoplastic survival
Immortal
*other features: evasion of senescence, evasion of mitotic crisis, self renewal
What are the 4 classes of regulatory genes–the principal targets of cancer causing mutations that tend to be affected in cancer?
Growth promoting Proto oncogenes
Growth inhibiting tumor suppressor genes, genes that regulated apoptosis, DNA repair genes
All are oncogenes if they are related to cancer development
At least some cells in all cancers must be stem cell like. How do these cancer stem cells arise?
Through transformation of a normal stem cell or through acquired genetic lesions that impart a stem-like state on a more mature cell. Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase which act together to convey limitless replicative potential
Definition of signal transduction pathway
A set of chemical reactions in a cell that occurs when a molecule such as a hormone attaches to a receptor on the cell membrane. The pathway is actually a cascade of biochemical reactions inside the cell that eventually reach the target molecule or reaction
Normal cellular genes whose products promote cell proliferation
Proto-ocogenes
mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals
Oncogenes
a protein encoded by an oncogene that drives increased cell proliferation through one of several mechanisms
Oncoprotein
Mechanisms by which oncoproteins drives increased cell proliferation:
- Constitutive expression of growth factors and their receptors–>autocrine signaling loop
- mutations in growth factor receptors like non-receptor tyrosine kinases or downstream signaling molecules that lead to constructive signaling
- increased expression of MYC–gene needed for rapid cell growth–via chromosomal translocation a (Burkitt lymphoma), Gene amplification (neuroblastoma), increased activity of upstream signaling
- mutations that increase the activity of cyclin-dependent kinase 4 (CDK4)/cyclin D which promote cell cycle progression
Examples of downstream signaling molecules that lead to constitutive signaling
- Activation of EGF RTK by point mutations (lung cancer); activation of HER2 RTK by gene amplification (breast cancer); activation of JAK2 tyrosine kinase by point mutation (myeloproliferative disorders)
- Activation of the ABL non-RTK by chromosomal translocation and creation of BCR-ABL fusion gene (chronic myeloid nous leukemia, acute lymphoblastic leukemia)
- Activation of PI3K and BRAF serine/threonine kinases by point mutations
Tumors arising in the context of chronic inflammation are usually what kind of cancers?
Carcinomas but also include mesothelioma and several kinds of lymphoma
Immunodeficiency states tend to predispose to what kind of cancers?
Virus-induced cancers
Carcinomas, the most common general category of cancer in adults are extraordinarily RARE in ____
Children
When cancer occurs because of an inherited gene mutation, it is referred to as ______. Examples?
Heriditary cancer
Examples: mutations of BRCA1 and BRCA2 are inherited and substantially increase the risk of breast and ovarian cancer
By the time a tumor comes to clinical attention (1gm or 10^9 cells), it has gone through a minimum of ____ divisions
30
(Likely an underestimation since many cells die via apoptosis and due to Darwinian selection of the fittest for nutrients, etc)
The promiscuous tendency of tumors to become more aggressive over time due to selective pressure is called _______
Tumor progression
As a tumor cell population expands, a progressively ____ percent of tumor cells leave the replicating cellular pool
Higher
What does the tumor evolution of a renal carcinoma tell us?
The mutation constituency tends to vary from the original site and even varies between metastatic sites or locales
One of the most profound selective pressures that cancer cells face is ________
Chemotherapy or radiotherapy
*tumors that recur after therapy are almost always found to be resistant if the same treatment is given again because therapy selects for pre existent subclones that by change have a genotype that allow them to survive
Genomic themes in carcinogenesis:
Non lethal genetic damage
Clinal expansion of single precursor cell
4 classes of regulatory genes affected: growth promoting Porto-oncogenes, growth inhibiting tumor suppressor genes, genes that regulate apoptosis, and DNA repair genes
In epigenetic modifications what determines the lineage commitment and differentiation state of both normal and neoplastic cells?
DNA methylation and histone modification dictates which genes are expressed which in turn determines the lineage and differentiation
Cell and molecular hallmarks of cancer
Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Altered cellular metabolism Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize Ability to evade host immune response
Genomic instability and cancer promoting inflammation tend to ____ the features or hallmarks of cancer
Accelerate
All cancers ultimately contain certain cells that are ____ and often exhibit other features related to neoplastic survival
Immortal
*other features: evasion of senescence, evasion of mitotic crisis, self renewal
What are the 4 classes of regulatory genes–the principal targets of cancer causing mutations that tend to be affected in cancer?
Growth promoting Proto oncogenes
Growth inhibiting tumor suppressor genes, genes that regulated apoptosis, DNA repair genes
All are oncogenes if they are related to cancer development
At least some cells in all cancers must be stem cell like. How do these cancer stem cells arise?
Through transformation of a normal stem cell or through acquired genetic lesions that impart a stem-like state on a more mature cell. Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase which act together to convey limitless replicative potential
Definition of signal transduction pathway
A set of chemical reactions in a cell that occurs when a molecule such as a hormone attaches to a receptor on the cell membrane. The pathway is actually a cascade of biochemical reactions inside the cell that eventually reach the target molecule or reaction
Normal cellular genes whose products promote cell proliferation
Proto-ocogenes
mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals
Oncogenes
a protein encoded by an oncogene that drives increased cell proliferation through one of several mechanisms
Oncoprotein
Mechanisms by which oncoproteins drives increased cell proliferation:
- Constitutive expression of growth factors and their receptors–>autocrine signaling loop
- mutations in growth factor receptors like non-receptor tyrosine kinases or downstream signaling molecules that lead to constructive signaling
- increased expression of MYC–gene needed for rapid cell growth–via chromosomal translocation a (Burkitt lymphoma), Gene amplification (neuroblastoma), increased activity of upstream signaling
- mutations that increase the activity of cyclin-dependent kinase 4 (CDK4)/cyclin D which promote cell cycle progression
Examples of downstream signaling molecules that lead to constitutive signaling
- Activation of EGF RTK by point mutations (lung cancer); activation of HER2 RTK by gene amplification (breast cancer); activation of JAK2 tyrosine kinase by point mutation (myeloproliferative disorders)
- Activation of the ABL non-RTK by chromosomal translocation and creation of BCR-ABL fusion gene (chronic myeloid nous leukemia, acute lymphoblastic leukemia)
- Activation of PI3K and BRAF serine/threonine kinases by point mutations
Tables 7-5 and 7-7
Need to know!!
All signal transduction pathways converge on the _____
nucleus
The most commonly involved nuclear regulatory proteins in human tumors?
MYC
The MYC proto-oncogene is expressed in virtually all eukaryotic cells and belongs to the ______ genes which are rapidly and transiently induced by _____ signaling following growth factor stimulation of quiescent cells
immediate early response genes
RAS/MAPK
Any organism whose cells contain a nucleus and other organelles enclosed within membranes
eukaryote
single celled organism that lacks a membrane bound nucleus, mitochondria, or any other membrane bound organelle
prokaryote
a small infectious agent that replicates only inside the living cells of other organisms. They can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea
virus
activates the expression of many genes involved in cell growth; upregulates expression of telomerase; can act to reprogram somatic cells into pluripotent stem cells
MYC
2 classes of MYC?
NMYC and LMYC
How is MYC deregulated in cancer?
mutation of MYC itself and amplification in other neoplastic settings
MYC associations with specific cancers?
Burkitt lymphoma, (and other B and T cell tumors), neuroblastoma, and many common carcinomas
Burkitt lymphoma chromosomal translocation
chromosome 8 and 14 (MYC oncogene is translocated to chromosome 14 which normally is on 8) which then leads to increased MYC protein leading to expression of pro-growth genes
What is the role of MYC in neuroblastoma?
The NMYC gene, normally present on chromosome 2p becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogenous staining region (HSR). The integration involves other autosomes such as 4, 9, or 13
Name the cell cycle inhibitor: blocks the cell cycle by binding to cyclin-CDK complexes
CIP/KIP family
induced by the tumor suppressor p53
p21, p27
p27 responds to growth suppressors such as TGF B
CDK1A-C
Familial syndromes and cancers associated with APC (mitogenic signaling pathways)
Familial colonic polyps and carcinomas,
sporadic: carcinomas of stomach, colon, pancreas; melanoma
Familial syndromes and cancers associated with NF1 (mitogenic signaling pathways)
Familial: Neurofibromatosis type 1 (neurofibromas and malignant peripheral nerve sheath tumors)
Sporadic: neuroblastoma, juvenile myeloid leukemia
Familial syndromes and cancers associated with NF2 (mitogenic signaling pathways)
Familial: Neurofibromatosis type 2 (acoustic schwannoma and meningioma)
Sporadic: meningioma
Tumor suppressive pocket protein that binds E2F transcription factors in its hypophosphorylated state, preventing G1/S transition; also interacts with several transcription factors that regulate differentiation. What familial and sporadic cancers is this protein associated with?
RB
Familial retinoblastoma syndrome (retinoblastoma, osteosarcoma, other sarcomas)
Sporadic: retinoblastoma; osteosarcoma carcinomas of breast, colon, lung
What familial and sporadic cancers is VHL associated with? (Inhibitors of pro-growth programs of metabolism and angiogenesis)
Familial: Von Hippel Lindau syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma)
Sporadic: Renal cell carcinoma
What familial and sporadic cancers is CDH1 (E-cadherin) associated with? (inhibitors of invasion and metastasis)
Familial gastric cancer
sporadic: gastric carcinoma, lobular breast carcinoma
What familial and sporadic cancers is TP53 associated with? (enablers of genomic stability; also a cell cycle component)
Familial:Li-Fraumeni syndrome (diverse cancers)
sporadic: Most human cancers
*TP 53 is the most common mutated gene and is associated with cell cycle checkpoint
Tumor suppressor altered in majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of this are negatively regulated by MDM2 through a feedback loop. This gene? (protein?) is also required for the G1/S checkpoint and is a main component of the G2/M checkpoint
p53
What familial and sporadic cancers is BRCA1 and BRCA2 associated with? (DNA repair factors)
Familial breast and ovarian carcinoma; carcinomas of male breast; chronic lymphocytic leukemia (BRCA2)
Sporadic: Rare!
What familial and sporadic cancers is WT1 associated with? (unknown mechanism)
Familial wilms tumor
sporadic wilms tumor, certain leukemias
Are gain of function mutations and loss of function mutations talking about the functions of the cell or the gene?
Gain of fnx/loss of fnx of the GENE!! NOT the cell! Gene expression NOT cellular expression!
What are the mechanisms by which RB is abrogated in cancers?
- Loss of function mutations affecting RB
- Gene amplifications of CDK4 and cyclin D genes
- Loss of cyclin dependent kinase inhibitors (p16/INK 4)
- VIRAL ONCOPROTEINS THAT BIND AND INHIBIT RB (E7 PROTEIN OF HPV)
How does RB govern the cell cycle?
When hypophosphorylated, RB exerts antiproliferative effects by binding and inhibiting E2F transcription factors that regulate genes required for cells to pass through the G1-S phase cell cycle checkpoint. Normal growth factor signaling leads to RB hyperphosphorylation and inactivation, thus promoting cell cycle progression
Pathogenesis of retinoblastoma
Two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the sporadic form, both RB mutations in the tumor-founding retinal cell are acquired. In the familial form, all somatic cells inherit one mutated copy of RB gene from a carrier parent and as a result only one additional RB mutation in retinal cell required for complete loss of RB fnx
The role of RB in regulating the G1-S checkpoint of cell cycle
Hypophosphorylated RB in complex with E2F transcription factors binds to DNA, recruits chromatin remodeling factors (histone deacytelases and histone methyl transferases) and inhibits transcription of genes whose products are required for the S phase of the cell cycle. WHen RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin ECDK2 complexes, it releases E2F. The latter then activates transcription of S phase genes. The phosphorylation of RB is inhibited by cyclin dependent kinase inhibitors, bc they inactivate cyclin CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosporylation of RB; these genes are RB, CDK4, genes encoding cyclin D proteins and CDKN2A
The ____ protein is the central monitor of stress in cells and can be activated by anoxia, inappropriate singaling by mutated oncoproteins, or DNA damage. It controls the expression and activity of proteins involved in cell cycle arrest, DNA repair, cellular senscence and apoptosis
p53
How does p53 cause cell cycle arrest thus allowing cells to repair DNA damage?
DNA damage is sensed by complexes containing kinases of the ATM/ATR family; these kinases phosphorylate p53, liberating it from inhibitors such as MDM2. Active p53 then upregulated expression of proteins such as the cyclin dependent kinase inhibitor p21, thereby causing cell cycle arrest at the G1-S checkpoint allowing cells to repair DNA damage
What does p53 do if DNA damage cannot be repaired?
p53 induces additional events that lead to cellular senescence or apoptosis
Majority of human cancers demonstrate _____ mutations in TP53.
biallelic loss of function
*Rare patients with Li-Fraumeni syndrome inherit one defective copy of TP53 and have a very high incidence of a wide variety of cancers
How is p53 inactivated?
Like RB, it is inactivated by viral oncoproteins, such as the E6 protein of HPV
The role of p53 in maintaining integrity of genome
activation of normal p53 by DNA damaging agents or by hypoxia leads to ccell cycle arrest in G1 and induction of DNA repair by transcriptional upregulation of the CDKN1A (encoding CDK inhibitor p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair falls, p53 triggers either apoptosis or senescence. In cells with loss or mutations of the p53 gene, DNA damage does NOT induce cell cycle arrest or DNA repair and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms
Mechanism of Action of tumor suppressor gene APC
encodes a factor that negatively regulates the WNT pathway in colonic epithelium by promoting the formation of a complex that degrades B-catenin
In which disorders are APC mutated?
Mutated in familial adenomatous polyposis, autosomal dominant disorder associated with development of thousands of colonic polyps and early onset colon carcinoma; tumor development associated with loss of single normal APC allele
Mutated in 70% of sporadic colon carcinomas; tumor development associated with acquired biallelic defects in APC
Normal APC function vs. mutated/absent APC
In resting colonic epithelial cells (not exposed to WNT), B catenin forms complex with APC protein which destroys B-catenin lowering levels of B cetenin. When normal colonic epithelial cells are stimulated by WNT the destruction complex is deactivated, and B catenin degradation does not occur and cytoplasmic levels increase. B-catenin translocated to nucleus where it binds to TCF, transcription factor that activates gene involved in cell cycle progression. When APC is mutated (colon cancer/polyps), the destruction of B-catenin cannot occur. B catenin translocates to nucleus and coactivates genes that promote entry into cell cycle and behave as if they are under constant stimulation by WNT pathway
encodes a component of a ubiquitin ligase that is responsible for degradation of hypoxia induced factors (HIF), transcription factors that alter gene expression in response to hypoxia
VHL
cancers associated with VHL mutation
Germline loss of function mutations cause von-Hippel Lindau syndrome, autosomal dominant disorder associated with high risk of renal cell carcinoma and pheochromocytoma
Acquired biallelic loss of mutations are commin in sporadic renal cell carcinoma
*CNS tumors, renal cysts, neuroendocrine tumors and renal cell carcinoma
BCR-ABL fusion gene
BCR-ABL–>activation of tyrosine kinase–>activation of growth factor signaling pathways (myelogenous leukemia–translocation of chromosomes 9 and 22)
Intrinsic and extrinsic pathways of apoptosis and mechanisms used by tumor cells to evade cell death
- Loss of p53 leading to reduced function of pro-apoptotic factors such as BAX
- Reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors such as BCL-2, BCL XL, MCL1
- Loss of apoptotic peptidase activating factor 1 (APAF)
- Upregulation of inhibitors of apoptosis (IAP)
- Reduced CD95 level
- Inactivation of death induced signaling complex
In cancer is evasion of intrinsic or extrinsic pathway more common?
intrinsic–lesions that incapacitate mitochondrial pathway more common in cancers
In greater that 85% of follicular B-cell lymphomas, the ___ gene is overexpressed due to a translocation (14 & 18)
anti-apoptotic gene BCL2
*overexpression of other BCL2 family members such as MCL-1 also linked to cancer cell survival and drug resistance
RB, a negative regulator of G1/S cell cycle transition is directly or indirectly inactivated in most human cancers. RB also controls cellular differentiation. Two mutations (hits) involving both alleles of RB at chromosome locus ____ are required to produce retinoblastoma
13q14
sporadic vs. familal cases of retinoblastoma
Familial: one defective copy already inherited (1st hit) in germline so if the normal allele of RB is spontaneously mutated somatically (2nd hit), you get retinoblastoma–autosomal dominant and can be unilateral or bilateral]
Sporadic–both copies must undergo somatic mutation–low probability
p53 stops neoplastic transformation by inducing cell cycle arrest, senescence (cell cycle arrest), or apoptosis. p53 can also inhibit _____and its positive effects stems from its ability to function as transcription factor
angiogenesis
What happens when p53 function is lost?
DNA damage is not repaired, mutations accumulate in oncogenes and other genes eventually leading to malignant transformation
p53 therapeutic implications
Irradiation and conventional chemotheraphy mediate their effects by inducing DNA damage and subsequent apoptosis. Tumors iwth wild type TP53 alleles are more likely to be killed by such therapy than tumors with mutated TP53 alleles like in testicular teratocarcinomas and childhood acute lymphoblastic leukemias which have wild type TP53 alleles. Other tumors like lung cancers and colorectal cancers have TP53 mutations making them resistant to chemotherapy and irradiation
Location of tumor suppressor genes is suspected by the detection of recurrent sites of _____
chromosomal deletions—found via high throughput sequencing of cancer genomes
Hypoxia triggers angiogenesis through the actions of ____ on the transcription of the proangiofactor ____
HIF-1a, VEGF
Other factors that regulate angiogenesis
p53 induces synthesis of angiogenesis inhibitor thrombospondin 1 while RAS, MYC and MAPK signaling upregulate VEGF expression and stimulate angiogenesis
____ inhibitors are used to treat many cancers and prolong the clinical course but not curative
VEGF
4 steps in ability to invade tissues, a hallmark of malignancy
loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components and migration of tumor cells
In invasion, cell-cell contacts are lost by the inactivation of ____
E cadherin
Basement membranes and interstitial matrix degradation is mediated by ____ secreted by tumor cells and stromal cells such as ____
proteolytic enzymes
MMPs
*proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic gragments from cleavage of ECM glycoproteins
The metastatic site of many tumors can be predicted by the location of the _____
primary tumor–many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly)
Why do some organs show tropism?
due to expression of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site
Genes that promote epithelial-mesenchymal transitions, like ____ and ____ may be important metastasis genes in epithelial tumors
TWIST and SNAIL
Normally, how are tumor cells destroyed?
the immune system recognizes it as non-self and destroys it
Antitumor activity is mediated by predominantly what mechansism?
cell-mediated mechanisms–tumor antigens are presented on the cell surface by MHC Class I molecules and are recognized by CD8+ CTLs
The different classes of tumor antigens include what?
products of mutated proto-oncogenes, overexpressed or aberrantly expressed proteins, tumor antigens produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins, and cell type-specific differentiation antigens
Immunosuppressed patients have an increased risk for cancer development. especially types caused by ____
oncogenic DNA viruses
In immunocompetent patients, tumors may avoid the immune system by mechanisms including:
selective outgrowth of antigen-negative variants, loss or reduced expression of histocompatibility antigens, and immuno-suppression mediated by expression of certain factors (e.g, TGF BPD-1 ligand, galectins) by the tumor cells
Proteins that are expressed at high levels on cancer cells and in normal developing (fetal) tissues. They are sufficiently specific that they can serve as markers that aid in tumor diagnosis and clinical management but they are also found at low levels in normal tissue and other inflammatory conditions
oncofetal antigens
examples of oncofetal antigens?
CEA (carcinoembryonic antigen) and AFP (alpha-fetoprotein)
Tumor cells expressing product of oncogene or mutated tumor suppressor gene example:
oncogene products: mutated RAS, BCR/ABL fusion proteins
Tumor suppressor gene products: mutated p53 protein
Tumor cells overexpressing or aberrantly expressing self protein example:
Overexpressed: tyrosinase, gp100, MART in melanomas
Aberrantly expressed: cancer-testis antigens (MAGE, BAGE)
Tumor cells expressing oncogenic virus examples:
Human papilloma virus, E6, E7 proteins in cervical carcinoma; EBNA proteins in EBV-induced lymphoma
Immune cells involved in anti-tumor effector mechanisms
CTL, NK cells and macrophages
Patients with ____ syndrome have defects in the mismatch repair system, leading to development of carcinomas of the colon. These patients genomes show microsatellite instability, characterized by changes in length of short repeats throughout the genome
HNPCC syndrome
Patients with ____ have a defect in the nucleotide excision repair pathway and are at increased risk for the development of cancers of the skin exposed to UV light bc of an inability to repair pyrimidine dimers
xeroderma pigmentosa
What syndromes are assoicated with defects in the homologous recombination DNA repair system?
Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia that are characterized by hypersensitivity to DNA damaging agents such as ionizing radiation.
BRCA1 and BRCA2 are genes involved in ____
DNA repair
Mutations due to expression of gene products that induce genomic instability (RAG1, RAG2, AID) are important causes of ____
lymphoid neoplasms—affects lymphoid cells
inflammation induced sequestration of iron and downregulation of erythropoietin production seen in some cancers
anemia
In patients with advanced cancers, inflammatory reaction can be so extensive as to cause systemic signs and symptoms such as what?
anemia, fatigue and cachexia
cachexia is seen in many cancer patients. Cachexia is progressive loss of body fat and lead body mass accompanied by profound weakness, anorexia, and anemia. What is cachexia associated with?
equal loss of both fat and lean muscle
elevated basal metabolic rate
evidence of systemic inflammation (increase in acute phase reactants)–strong association with TNF-a
COX-2 inhibitors
have been shown to decrease the incidence of colonic adenomas and are now approved for treatment of paitents with familial adenomatous polyposis
Balanced translocations contribute to carcinogenesis by? Deletions? Gene amplification?
-translocations: overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity.
-Deletions frequently cause loss of tumor suppressor gene function and occasionally activate proto-oncogenes.
Gene amplification generally increases expression and function of oncogenes
Genomic sequencing has revealed numerous cryptic (subcytogenetic) rearrangements. Examples?
small deletions and insertions (indels) as well as chromothrypsis, in which a chromosome is shattered and then reassembled in a haphazard way
Name the translocation and affected genes:
CML
(9,22); (q34,q11)
Affected genes ABL 9q34
BCR 22q11
Name the translocation and affected genes:
AML
(8,21); (q22,q22)–>AML 8q22
(15,17); (q22, q21)–>ETO21q22, PML 15q22, RARA 17q21
Name the translocation and affected genes:
Burkitt lymphoma
(8,14); (q24,q32)–>MYC 8q24
IGH 14q32
Name the translocation and affected genes:
Follicular lymphoma
(14;18); (q32;q21)–>IGH 14q32, BCL2 18q21
Name the translocation and affected genes:
Ewing sarcoma
(11,22) (q24;q12)–>FLI1 11q24, EWSR1 22q12
Name the translocation and affected genes:
prostatic adenocarcinoma
(7,21) (p22q22)–>TMPRSS2 (21q22.3)
17;21) (p21;q22)–>ETV1 (7p21.2), ETV4 (17q21
colorectal cancer progression
- Germ line or somatic mutations of cancer suppressor genes (first hit)=APC at 5q21–>mucosa at risk
- Methylation abnormalities, inactivation of normal alleles (second hit)=APC B-catenin–>adenomas
- Proto-oncogene mutation=KRAS at 12p12–>adenomas
- Homozygous loss of additional cancer suppressor genes (TP53 at 17p13; LOH at 18q21; SMAD 2 & 4)–>carcinoma
- Additional mutations, gross chromosomal alterations (telomerase, many other genes)–>carcinoma
non-coding RNAs that do not encode proteins; instead they function primarily to modulate the translation of target mRNAs into their corresponding proteins. Posttranscriptional silencing of gene expression by miRNA is a fundamental and well conserved mechanism of gene regulation present in all eukaryotes
micro-RNA (miRNA)
non-coding RNAs that modulate gene expression in many ways–for example they can bind to regions of chromatin, restricting RNA polymerase to coding genes within the region
lncRNAs
Mechanism where the MICROSTRUCTURE (NOT CODE) of DNA itself or the associated chromatin proteins may be modified causing activation or silencing
epigenetics
nuclei of cancer cells show abnormal morphologies like what?
hyperchromasia, chromatin clumping or chromatin clearing
mutation of regulator gene MLL1 and MLL2 is related to what cancers?
MLL1–acute leukemia in infants (90%)
MLL2–follicular lymphoma (90%)
Both mechanisms=histone methylation
mutation of regulator gene SNF5 is related to what cancers?
Malignant rhabdoid tumor (100%)
epigenetic mechanism=nucleosome positioning/chromatin remodeling
Steps in initiation vs. promotion
*Most carcinogens require metabolic activation for conversion into ultimate carcinogens
Initiation: Carcinogen–>electrophilic intermediates–>binding to DNA: Adduct formation–>permanent DNA lesion:initiated cell
Promotion: –>cell proliferation: altered differentiation–>preneoplastic clone–>malignant neoplasm via additional mutations/proliferation
People of European origin who have fair skin that repeatedly become sunburned and who live in locales recieving a great deal of sunlight (Queensland, australia, close to equator) have the highest incidence and risk for what kinds of cancer?
skin cancers–melanomas, squamous cell carcinomas, basal cell carcinomas
difference between melanomas and nonmelanoma skin cancers
nonmelanoma=associated with total cumulative exposure to UV radiation
melanoma=associated with intense intermittent exposure (sunbathing)
The carcinogenicity of UVB light is due to?
formation of pyrimidine dimers in DNA
Radiation induced cancers by frequency:
myeloid leukemias (tumors of granulocytes and precursors) are most frequent followed closely by thyroid cancer but only in the young intermediate=breast, lung and salivary gland
skin, bone and GI tract are relatively resistant to radiation induced neoplasia even through the GI epithelial cells are vulnerable to acute cell killing effects of radiation and the skin is frst in line for all external radiation
What cancers are the following RNA viruses associated with?
HTLV-1, HPV, EBV (and burkitt lymphoma), HBV (and HCV), Merkel cell polyomavirus, HHV-8
Why isnt HIV listed here?
HTLV1--T cell lymphoma HPV--cervical cancer EBV and Burkitt lymphoma HBV (and HCV)--hepatocellular carcinoma HHV-8--Large B cell lymphoma and Kaposi sarcoma? helicobacter pylori??
HIV IS NOT A TRANSFORMING VIRUS!! the rest of thes are!
Benign and malignant neoplasms arising in endocrine glands can cause clinical problems by producing hormones. Such activity is more typical of benign or malignant tumors?
Benign tumors because malignant tumors may be so undifferentiated that they have lost such capablity
*example of benign tumor that can kill you:
schwannoma at CPA can compress brainstem and compress respiratory centers and can kill you even though it is benign
Endocrinopathy: hypercalcemia–major forms of underlying cancer and causal mechanisms
Squamous cell carcinoma of lung, breast carcinoma, renal carcinoma, adult T cell leukemia/lymphoma
Caused by parathyroid hormone related protein (PTHRP), TGFa, TNF and IL1
Nerve and muscle syndrome: acanthosis nigricans–major forms of underlying cancer and causal mechanisms
Gastric carcinoma, lung carcinoma, uterine carcinoma
Causal factor: immunoloic, secretion of epidermal growth factor
Osseous, articular and soft tissue changes: Hypertrophic osteoarthropathy and clubbing of the fingers–major forms of underlying cancer and causal mechanisms
Bronchogenic carcinoma, thymic neoplasms
mechanism=unknown
progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia, that is caused by release of factors by the tumor or host immune cells
cachexia
symptom complexes in individuals with cancer that cannot be explained by tumor spread or release of hormones that are indegenous to the tumor cell of origin
Paraneoplastic syndromes
Examples of paraneoplastic syndromes?
Endocrinopathies: cushing syndrome, hypercalcemia
Neuropathic syndromes: polymyopathy, peripheral neuropathy, neural degeneration, myasthenic syndromes
Skin disorders: (acanthosis nigricans)
skeletal and joint abnormalities (hypertrophic osteoarthritis)
Hypercoagulability: migratory thrombophlebitis, DIC, nonbacterial thrombotic endocarditis
How are tumors graded?
determined by cytologic appearance; based on the idea that behavior and differentiation are related, with poorly differentiated tumors having more aggressive behavior
How are tumors staged?
determined by surgical exploration or imaging–based on size local and regional lymph node spread and distant metastases; of greater clinical value than grading
Classification of cancer according to therapeutic targets rather than cell of origin:
Lung, Breast, Prostate, colon, brain
lung--mutated KIT Breast--mutated HER2 Prostate--mutated EGFR Colon--mutated BRAF BRain--mutated PI3K
Know Table 7-12!!
slide 108
