park-neoplasia Flashcards
neoplasia
-dysregulated cell proliferation
-abnormal growth of cells or tissue
What are the two types of neoplasia?
malignant tumors (cancers)
benign tumors
Malignant tumors
-large
-poorly demarcated
-rapidly growing with hemorrhage and necrosis
-locally invasive
-metastatic
-poorly differentiated
benign tumors
-small
-well demarcated
-slow growing
-noninvasive
-non metastatic
- well differentiated
Naming of benign tumors
-adding the suffix -oma to the parenchymal tissue type
-ademona (glands), osteoma (bones), hemangioma (blood vessels), leiomyoma (smooth muscle), neuroma (neurons), glioma (glial cells)
Naming malignant tumors
-carcinoma
-sarcoma
-leukemia
-blastoma
carcinoma
-malignant tumor of epithelial tissue origin
-adenocarcinoma
sarcoma
-malignant tumor oc connective, muscle, endothelial tissues
-osteosarcoma, leiomyosarcoma, hemangiosarcoma
leukemia
-malignant tumor of blood cells
blastoma
-malignant tumor of precursor cells
-neuroblastoma, glioblastoma, retinoblasta
What are characteristics of cancer cells
-loss of cell differentiation
-genetic instability
-growth factor independence
-loss of cell density-dependent inhibition
-anchorage independence
-faulty cell-to-cell communication
-unlimited life span
-antigen expression
-abnormal production of proteins, hormones, etc
-cytoskeletal changes
loss of cell differentiation (anaplasia)
-resemblance to undifferentiated or embryonic cells
genetic instability
-aneuploidy (loss of gain of chromosomes)
-intrachromosomal instability (insertions, deletions, and amplifications of genes)
-micro satellite instability (short, repetitive sequences of DNA)
-point muations
growth factor independence
proliferation even in the absence of growth factors
loss of cell density-dependent inhibition
-lack of contact inhibition
-rampant growth without regard for adjacent tissue
-necessary fro invasion
anchorage independence
-cancer cells frequently remain viable and multiply without normal attachments to other cells and the extracellular matrix
-critical for metastasis
faulty cell-to-cell communication
formation of intracellular connections and responsiveness to membrane-derived signals are frequently interfered in cancer cells
unlimited life span
cancer cells can divide unlimited number of times
antigen expression
-cancer cells express many cell surface molecules or antigens that are immunologically identified as foreign (tumor antigens)
-ex. fetal proteins that are not expressed by the comparable cells in adult
-tumor antigen may be clinically useful as cancer biomarkers
abnormal production of proteins, hormones, etc
-cancer cells secrete degradative enzymes that enable invasion and metastatic spread
-cancer cells may synthesize hormones that promote their own growth (ex estrogen production by breast cancer)
-cancer cells may produce and secret procoagulant substances that affect clotting mechanisms
cytoskeletal changes
-changes in intermediate filament, actin filaments, and microtubules
-abnormal cell morphology
-facilitate invasion and metastasis
grading
-determined by microscopic examination of tumor cell morphology (histologic analyses)
-samples for these analyses can be obtained by excision or biopsy, fine needle aspirations, or cytologic (pap) smears
-largely qualitative in nature
-based on the differentiation state and the number of mitoses of the tumor
list the different grades
-grade X (grade cannot be assessed/ undetermined grade)
-grade I (well differentiated/ low grade)
-grade II (moderately differentiated/ intermediate grade)
-grade III (poorly/ high grade)
-grade IV (undifferentiated/ high grade)
two major classes of genes
-oncogenes- genes that encode the proteins that promote cancer
-tumor suppressor genes- genes that encode proteins that inhibit cancer
staging
-base don size of the primary lesion (T), extent of spread to lymph nodes (N), and the presence or absence of metastasis (M)
-largely quantitive in nature
-of greater clinical value
Fundamental principles of carcinogenesis
-genetic changes (mutations)
-two major classes of genes are the targets of this damage
-often a multistep process wth multiple genes involved
two hit hypothesis
-assumption that retinoblastoma requires two mutations
-this hypothesis accurately predicts the number of cases of the cancer over time in hereditary and nonhereditary retinoblastoma
describe the TNM system
-tumore, node, metastasis
-T0-T4
-N0-N3
-M0-M1
retinoblastoma
-some cancers are the result of mutation or deletion of a single gene, and these cancers tend to run in families
-retinoblastoma is a childhood retinal cancer; during development, retinal cells don’t stop dividing when they are supposed to, which results in tumors
-carriers of a mutation in a gene (RB1 a tumor suppressor gene) show increased susceptibility to the cancer (hereditary retinoblastoma) compared with non-carriers (nonhereditary retinoblastoma)
-if bilateral there is a 25%-30% chance of being hereditary and a 0% chance of being nonhereditary
-if unilateral there is a 10%-15% chance of being hereditary and a 55%-65% chance of being nonhereditary
tumor suppressors
-two mutations required for retinoblastoma are the mutation both alleles of the same gene (RB1) which is a tumor suppressor
-the carriers already have a recessive genetic mutation in one allele; one more mutation on the other allele (one hit) can cause the cancer
-non-carriers require mutations on both allele (two hits) to develop the cancer
-most tumor suppressors are recessive and need homozygous deletion/mutation on both alleles
-RB1 and TP54 (gene of p53)
-heterozygous mutations in tumor suppressor genes can be inherited, and families show increased susceptibility to cancer
oncogenes
-altered genes that drive cancer
–translocation that makes a protein with a new function (BCR-ABL)
–mutation that makes a more active version of protein (K-Ras)
–gene duplication and over expression of a normal protein involved in cell growth
-these alterations are dominant and often occur at a single allele
-the normal version is called a “proto-oncogene” (denoted by C-gene)
-BCR-ABLe protein results as a chromosomal translocation. It produces a hyperactive kinase that drives proliferation in leukemia
pediatric cancers
-tend to have single genetic events (mutations, translocations) that are important at a specific developmental time
-if carriers of RB1 do not develop the cancer as children, they won’t get it all (but will pass it on)
adult cancers
-rarely have just a single genetic mutation
-tend to be more hetergenous
-patients have different combinations of mutations
risk factors of cancers
-epidemiological studies of cancer incidence discovered several risk factors of cancers
-age, environmental factors, genetics, inflammation, viruses
age
-cancers frequently require multiple mutations and often take 20 years or more to develop
-two common causes
–accumulation of somatic mutations
–decline in immune function
environmental factos
-the time required for cancer development with the increased mutation rate
–smokers develop lung cancers much faster than non-smokers
-examples: carcinogens, UV radiation, long radiation (X-ray, decay of radioactive isotopes)
carcinogens
-agents that can induce the genetic changes characteristic of tumors
-most carcinogens (or their metabolites) react with DNA, which leads to mutations and DNA damage
-examples: mustard gas, n-nitroso compounds (R-N-N=O) in cured meat, chemotherapy, benxo[a]pyrene from coal tar and cigarette smoke
genetics
-inherited mutations in tumor suppressor genes
-many are DNA repair genes
-BRCA1/2, XP, ATM, BLM
BRCA1/2
-function= double-strand break repair
-cancer= ovarian/breast
XP (xeroderma pigmentosum)
-function= nucleotide-excision repair
-cancer= skin cancer
ATM (ataxia telangiectasia)
-function= double strand break repair
-cancer= lymphoma and leukemia
BLM (blooms syndrome)
-function= DNA helicase
-cancer= various
inflammation
-chronic inflammation results in persistent regenerative cell proliferation or hyperplasia and DNA damage by reactive oxygen and nitrogen species produced by immune cells
-long unhealed skin wounds characterized by persistent damage can lead to skin cancer
-cirrhosis of the liver can lead to hepatocellular carcinoma
-chronic gastrits due to a long-standing H. pylori infection can lead to gastric cancer
-chronic ulcerative colitis can lead to colorectal cancer
viruses
-mechanisms
–integration into the genome (retroviruses) can cause modulation of oncogenes or tumor supressor genes
–chronic inflammation caused by HBV or HCV increases the risk of liver cancer
–viral proteins may alter cellular pathways…inactivation of tumor suppressors (ex E6 in HPV) or disruption of the normal cell-cycle control
oncogenic DNA viruses
-epstein barr virus (EBV
-kaposi’s sarcoma-associated herpesvirus (KSHV)
-human pailomavirus (HPV)
-merkel cell polyomavorus (MCPV)
-hepatitis B virus (HBV)
oncogenic RNA viruses
-hepatitis C virus (HCV)
-human T cell lymphotropic virus type I (HLTV1)
Human papillomavirueses (HPV)
-cause cervical cancer in women of all ages
-two viral proteins, E6 and E&, inactivate tumor suppressors, p53 and pRb respecitively
hallmarks of cancer
-self sufficiency in growth signals
-insensitivity to anti growth signals
-tissue evasion and metastasis
-limitless replicative potential
-sustained angiogensis
-evading apoptosis
several hallmarks relate to control of cell-cycle
-G0/G1
-S
-G2
-M
G0/G1
-cell is quiescent or accumulating “building blocks” required for division
-cellular content, excluding the chromosomes are duplicated
S
-cell replicating DNA
-each of the 46 chromosomes is duplicated by the cell
G2
-cell assembling machinery for chromosomal segregation and cytokinesis
- the cell “double checks” the duplicated chromosomes for error, making any needed reapairs
M
mitosis
cell cycle clock
-determines when the cells move from one phase of the cell cycle to the next
-driven by cyclins paired with cyclin dependent kinases (CDKs)
-R point (restriction point) is the critical time point when cell decide whether or not to enter the cell cycle
cell cycle checkpoints
-black the passage into the next cycle when cells are not ready
Hallmark #1 - self sufficiency in growth signals
-activation of kinase signal transduction pathways that respond to mitogenic signaling (growth factors)
-growth factor receptors are receptor tyrosine kinases (RTKs)
-activation of a receptor tyrosine kinase
–gain of function mutation in a receptor tyrosine kinase (ex EGFR in lung cancers)
–amplification of a receptor tyrosine kinase (ex HER2 in breast cancers)
activation of RTK signaling pathways
-cancer mutations are common in receptor tyrosine signaling pathways
-activation of oncogenes
–RTK (kinase)
–Ras (small GTPase)
–B-Raf (kinase)
–P13K (kinase)
–AKT (kinase)
-inactivation of tumor suppressors
–PTEN (phosphatase)
–TSC (GTPase activating protein)
Hallmark 2 - resistance to growth inhibitory signals
-cancer may arise through loss of expression (mutation) or growth inhibitory proteins (tumor suppressors)
Hallmark 3- evading apoptosis
-disruption of apoptotic pathways prevents cell death upon DNA damage or cell cycle checkpoint activation
-tumor suppressors
–p53 (transcription factor)
–p21 (CDK inhibitor / cell cycle checkpoint)
-BAX (pro-apoptotic regulator)
Hallmark 4- limitless replicative potential
-normal cells can divide only 40-60 times (hay flick limit)
-telomere shortening leads to chromosomal abnormalities (loss of genes near end of chromosomes) and cell death
-tumor cells over express telomerase, leading to cell immortalization
Hallmark 5- sustained angiogenesis
-tumor cells can trigger angiogenesis (neovascularization)
-solid tumors cannot grow beyond 1-2 mm diameter without blood supply
–deficient in oxygen and nutrient supplies
–unable to get rid of metabolic waste (lactic acid and carbon dioxide)
-tumor cells produce VEGF (vascular endothelial growth factor) to promote angiogenesis
Hallmark 6- tissue invasion and metastasis
- adhesion and invasion of basement membrane
- passage through extracellular matrix
- invasion of vascular basement membranes and vascular ingress (intravastion)
- travel via the vasculature)
- adhesion to basement membrane at destination
- invasion of vascular basement membrane and vascular exit (extravasation)
- metastatic deposit
- angiogensis and growth
multistep carcinogenesis
-initiation
-promotion
-progression
initiation
-exposure of cells to appropriate doses of carcinogenic agent
-irreversible changes in the genome
-the amount of total exposure matters
promotion
-unregulated and accelerated growth of the mutated cells
-triggered by growth factors and chemicals
-may occur after long latency periods
progression
acquisition of malignant characteristics (invasiveness, metastatic, competence)
tumor microenviornment
-has an important role in the development of cancer and metastasis
–in some cases, the phenotype of a cancer cell can normalize when it is removed from the tumor microenvironment and placed in an normal environment
-components
–multiple cell types, including macrophages, fibroblasts, endothelial cells, and a variety of immune and inflammatory cells
-extracellular matrix and primary signaling substances such as cytokines, chemokines, and hormones
systemic manifestations
-wasting syndrome (cancer anorexia-cachexia syndrome)
-fatigue and sleep disorder
-anemia
-pain
-wasting syndrome (cancer anorexia-cachexia syndrome)
-reduced food intake (anorexia) and wasting of body fat and muscle tissue (cachexia)
-oral or parenteral nutritional supplementation does not revers cachexia
-significant cause of morbidity and mortality
fatigue and sleep disorder
-tiredness, weakness, and lack of energy not relieved by rest or sleep
-poor sleep quality, insufficient sleep, nighttime awakening, and restless sleep
anemia
-blood loss, hemolysis, impaired red blood cell production
-drugs used in the treatment may also decrease red blood cell production
pain
-common in late-stage cancers
-the most dreaded aspects of cancer
-pain management is necessary even for patients with incurable cancers
molecular diagnosis
-identification of molecular causes of cancer
-methods
–fluorescence in situ hybridization (FISH) to estimate the gene copy number
–immunohistochemistry (IHC) to assess protein expression and tissue distribution
–DNA sequencing
-targeted cancer therapy
–BCR-ABL translocation (BCR-ABL inhibitors such as imanitib/Gleevec)
—estrogen receptor [ER] (expression in breast cancer..anti -hormone therapy)
—HER2 overexpression (anti-HER2 antibodies such as trastuzumab/ Herceptin)
–EGFR mutations (EGFR inhibitors)
–Ras mutation (targeted inhibitors)
cancer biomarkers
-proteins that are highly expressed in cancer tissues can also be used as biomarkers in blood
—PSA (prostate specific antigen) in prostate cancer
–APF (alpha fetoprotein) primarily liver cancer and germ cell cancer of testes
—CA 125 (cancer antigen 125) ovarian cancer
-not so useful for diagnosis due to the high false positive rate
–levels can be elevated by other causes than cancer
–can be used in combination with other diagnostic approaches
-useful in monitoring treatment response and recurrence
–decrease after sugery or treatments confirms the effectiveness
–increase later may suggest tumor recurrence
Which of the following is a correct description for benign tumors?
A. well differentiated
B. invasive
C. metastatic
D. rapidly growing
E. poorly demarcated
A. well differentiated
Which of the following tumors is malignant?
A. hemangioma
B. adenoma
C. neuroblastoma
D. glioma
C. Neuroblastoma
Which of the following is a necessary characteristics of cancers for metastasis?
A. anaplasia
B. aneuploidy
C. anchorage independence
D. unlimited life span
E. antigen expression
C. anchorage independence
The staging of a cancer is T3N1M0. Which of the following descriptions is correct about this cancer?
A. The size of the tumor is very small
B. the tumor has already spread to many local lymph nodes
C.The distant metastasis is not present yet
D. the cancer cells are undifferentiated
E. The cancer cells are well differentiated
C. The distant metastasis is not present yet
____ is a type of cancer originated from epithelial tissues.
A. epithelioma
B. carcinoma
C. sarcoma
D. leukemia
E. blastoma
B. carcinoma
Which of the following statement on carcinogenesis is incorrect?
A. oncogenic mutations are mostly dominant
B. mutations inactivating tumor suppressor genes are mostly recessive
C. adult cancers usually require mutations in multiple genes
D. gene duplication and over expression of a normal protein may cause cancer
E. proto-oncogenes are also tumor suppressor genes
E. proto-oncogenes are also tumor suppressor genes
carriers of a mutation in the RRB1 gene show increased susceptibility to retinoblastoma because___
A. just one more mutation in the other allele can cause the cancer
B. the protein expressed from the mutated RB1 gene interferes with the DNA repair
C. the protein expressed from the mutated RB1 gene acts as a growth factor
D. the mutation in the RB1 gene causes translocation of the chromosome
E. the protein expressed from the intact RB1 is not sufficient to prevent the cancer
A. just one more mutation in the other allele can cause the cancer
long standing H. pylori infection may cause gastric cancer. Which of the following risk factors of cancers explains this observation?
A. age
B. environmental factors
C. genetics
D. inflammation
E. viruses
D. inflammation
which of the following is not an example of environmental factors?
A. smoking
B. UV radiation
C. exposure to X-ray
D. N-nitrosos compounds
E. Defective DNA repair system
E. defective DNA repair system
Oncogenic mutations that create the constitutively active K-Ras belong to ___
A. loss-of function mutations
B. gain-of-function mutations
C. over expression
D. translocation
E. gene activation
B. gain-of-function mutation
Which of the following is not a hallmark of cancers?
A. evading apoptosis
B. self-sufficiency in growth signal
C. dependence on growth inhibitory signal
D. limitless replicative potential
E. sustained angiogenesis
C. dependence on growth inhibitory signal
Which of the following is not a oncogene but a tumor suppressor?
A. HER2 (receptor tyrosine kinase)
B. Ras (small GTPase)
C. P13K (kinase)
D. PTEN (phosphatase)
E. AKT (kinase)
D. PTEN (phosphatase)
How do cancer cells commonly acquire limitless replicative potential?
A. over expression of HER2
B. over expression of telomerase
C. gain-of-function mutation of Ras
D. loss-of-function mutation of p53
E. formation of BCR-ABL by translocation
B. over expression of telomerase
What is the normal function of VHL (von Hippel-Lindau tumor suppressor) in angiogensis?
A. hydroxylation of HIF
B. transcriptional activation of VEGF
C. inhibition of PHD
D. binding to VEGF
E. polyubiquitination of hydroxylated HIF
E. polyubiquitination of hydroxylated HIF
