09.27-30 Neoplasia Flashcards
(47 cards)
1
Q
metaplasia
A
- subsitution of one type of adult cells by another type
- may result from chronic irritation, impaired nutrition or altered function
- may lead to neoplasia (metaplasia is still benign)
2
Q
hyperplasia
A
cells stimulated to re-enter the cell cycle from G0 to G1
- prominent nucleoli
- basophilic cytoplasm (due to increase in RNA)
- mitotic figures (cells in different stages of mitosis) visible in the images
3
Q
neoplasia
A
- autonomous new growth (no need growth signal)
- a form of hyperplasia, with a heritable abnormality in the affected cells
- paraneoplastic syndromes
- diverse effects of neoplasm on host including effects on GI, bones, muscles, skin, etc.
- some due to secretion of unknown substances by neoplasm (cytokines, etc).
4
Q
dysplasia
A
- atypical cell types
- loss in the uniformity of individual cells
- loss of architectural orientation
- Barrett’s esophagus: intestinal metaplasia in the esophagus, mostly due to heart burns.
5
Q
benign tumors
A
- nomenclature: histogenesis+”oma”
- exceptions: adenoma (derived from and produce gland patterns), papilloma (projection on a surface).
- localized expensile masses
- usually encapsulated
- rarely become maglignant
- still can kill: pressure effect on brain or excess hormone production (hormone glands).
- ex) acute myeloid leukimia (AML): precursors do not differentiate and crowd out the space in bone marrow.
6
Q
cancer
A
- malignant neoplasia with capacity for infinite growth and dissemination
- “carcinoma-in-situ” if not invaded beyond basement membrane.
- “pearls” squamous epithelium that looks white-pearl-ish
- small-cell carcinlma: looks like black oat-grains
- anaplasia: marker for cancer. loss of normal cellular organization
- metastasis: distal-spread of the cancer from one location to the other.
- colon goes to liver.
- breast goes to bone
7
Q
cancer nomenclature
A
- sarcomas: arising from mesenchyme or derivative (connective tissue)
- carcinomas: epithelial origin (any of the three germ layer)
- malignant teratomas: contain cells derived from mor ethan one germ layer.
- choristoma: tumor-like masses of heterotopic tissue (e.g., pancreatic glands in gastric mucosa).
- hamartoma: abnormal mixture of tissues normally present in the involved area (e.g., a mass of cartilage tissue in bronchus). may represent expansion
8
Q
anaplasia
A
- loss of resemblance to differentiated cell
- pleomorphism: many different shapes and sizes.
- giant cells (multi-nucleated)
- high nuclear:cytoplasmic ratio (large nucleus)
- clumped and prominent chromatin (also observed in apoptosis)
- prominent nucleoli
- abnormal mitotic figures (multi-polar mitosis)
- distorted architecture
9
Q
cancer pathobiology: escape from normal control mechanisms
A
- aerobic glycolysis (Warburg hypothesis): produce lactic acid in presence of O2
- “glucose hunger” detectable by PET scan
- pyruvate is reutilized by tumor for anabolic reactions
- LKB1, a TS gene, mutated in Peutz-Jegher S (GI tumor) activates AMP-dependent protein kinase, a sensor for cellular status. lack of this action allows uncontrolled metabolism. (ATP > ADP > AMP).
- loss of contact inhibition
- infinite life span and increasd growth potential.
10
Q
cancer pathobiology: alteration in cellular membranes
A
- increased agglutinability by lectins
- new surface antigens
- lower cell-to-cell cohesion
- ability to grow in “soft agar”
11
Q
cell proliferation overview
A
- microenv’t must be suitable
- limiting steps (checkpoints) in cell cycle
- nutrients
- growth factors
- neoplastic cells have reduced or no need for above four.
12
Q
Breast cancer: inherited predisposition
A
BRCA1 gene
- susceptibility to bresat and ovarian cancer
- women with germ-line BRCA1 mutation have 85% of lifetime risk (half before age of 50)
- mutant allele is recessive (when wt is lost later in life, tumor develops)
- familial disease: more than 1 member of family and disease developed at younger age than non-genetic disease.
13
Q
A
14
Q
colon cancer: sporatic cancer
A
- colon cancers are mostly sporatic although some are inheritable.
- most arise from benign adenomas (polyps) that gradually increase in size, dysplasia and villous morphology.
15
Q
genes involved in colon cancer
A
- APC mutation >> hyperproliferating epith.
- DNA hypomethlation: early adenoma
- K-RAS activation >> intermediate adenoma
- DCC loss >> late
- p53 loss >> carcinoma
16
Q
APC gene
A
- platform for breakdown of beta-catenin and stimulates migration of colon cell from bottom of the crypt to the top, eventually to be shed.
- in normal embryonic cell, Wg-Wnt pathway inactivates APC and cell proliferates.
- in cancer cells, mutated APC gene leads to no breakdown of beta-catenin which induces proliferation and blocks apoptosis.
17
Q
tumor supressor gene overview
A
- TS gene encodes proteins which act as negative regulators of tumor growth.
- cancer predisposing alleles carry mutations that cause loss of reduction of gene function.
- a single inherited copy of the mutant alllel causes predisposition >> loss or inactivation of WT allele later in life result in neoplasia.
18
Q
TS gene function
A
- arrest unnecessary cell proliferation (control cell cycle)
- help to eliminate unnecessary cells (induce apoptosis)
19
Q
specific TS genes
- p27
- RB
A
- p27 inhibits going from G1 to S
- RB negatively regulates growth by binding to E2F which is needed for S phase transcription.
20
Q
frequently mutated genes and proteins
A
- p53, pRB, and p16 are most frequently mutated in cancers.
- there are other genes in the family with similar functions but the above genes are the best.
21
Q
dominant-negative pattern
A
- depending on the part of the gene that is mutated, a TS gene can be either recessive or dominant-negative.
p53 gene controls the cell cycle at G1 and G2 check points
- p53 is a transcriptional factor and work as a dimer
- homodimer p53 works well
- heterodimer p53
- if mutaed part disrupts the DNA-binding domain of the protein, the protein cannot work as transcriptional factor. the mutated protein tends to dimerize with WT protein >>dominant-negative.
- if mutated part donot disrupt DNA-binding domain, the protein is functional and the mutated allele is recessive.
22
Q
von Hippel-Lindau disease
A
von Hippel-Lindau disease
- normally pVHL degrades HIF (with oxygen)
- in hypoxia or pVHL mutation, HIF (hypoxia-inducible factor) activates genes that increase oxygen supply to the cell and induce migration/remodeling of the cell
23
Q
TGF-beta related genes in cancer
A
TGF beta-related genes in cancer
DPC4 gene is mutated in approx. 50% of pancreatic carcinomas. the gene closely resembles SMAD gene which participates in TGF-beta-like signal transduction pathway
SMAD genes are phosphorylated in time-dependent manner by TGF-beta
in 100% of colon and 83% of pancreatic cancers, at least one component of TGF-beta pathway is mutated.
24
Q
cancer recap
- activated proto-oncogenes
- TS
- cell death controlling genes
A
- activated proto-oncogenes
- unactivated: required for growth and differentiatoin in normal cells
- when activated: growth stimulatory and dominant action
- TS (“anti-oncogenes”)
- recessive (e.g., Rb gene)
- dominant negative (e.g., p53)
- cell death controlling genes
- suppression of apoptosis (e.g., Bcl-2)
- enhancement of apoptosis (e.g., Bax)
- miRNA
25
miRNA
* small non-coding RNAs that silence coding mRNAs
* miRNA loci can be subject to mutation: amplification or deletions
* miRNA can increase expression of oncogenes or reduce expression of TS genes
* e.g., miR 32 works on pro-apoptic BIM
* a TS gene can activate transcription of miRNA
* p53 activates miR34 family
26
oncogenes: cell proliferation
* normal: microenv't must be suitable and need nutrients and growth factors
* neoplastic: reduced need for external signals and limiting steps are more easily traversed.
* normal human cells have growth regulatory cells, often tissue-specific. mutations on these genes (activation of oncogenes) leads to inapproriate growth in inappropirate place.
27
oncogene mechanisms: RAS
* RAS is normally inactive and contains GDP
* when a growth factor receptor on the cell receives GF, the cascade starts \>\> binding protein binds the intracellular component of the receptor and activates RAS
* RAS replaces GDP with GTP and interacts with RAF-1 and and GAP which activates the MAP-kinase pathway, ultimately leading to activation of transcription and cell cycle progression.
* in a mutated RAS (p21), codon 12 is changed and the aa for the mutated RAS at codon becomes val.
28
oncogene mechanisms: epidermal growth factor (EGF) family
* ERBB1 (EGF receptor gene), ERBB2 )Her-2/NEU) and ERBB4 (HER-4) are most frequently mutated genes in the family
* mutations found in many cancers
* HER-2 (NEU/ERBB2) gene is amplified in 28% of primary bresat carcinomas, while another 10% overexpresses HER-2 without amplification of the gene.
29
cancer and virus
* a retrovirus, when it invades a host cell, can pick up a proto-oncogene.
* when the host cell releases more retroviruses, the viruses with the proto-oncogenes in their genome are also released (transforming retrovirus)
* when the transforming retrovirus invades another host cells and insert their genome in the host genome, the proto-oncogene may be activated into oncogenes
* rare in human but more common in birds (avian hematopoietic neoplasia)
30
cancer and genetic rearrangement
* when chromosome break and reattach incorrectly, proto-oncogene may get a strong promoter near its site and become activated.
31
genetic rearrangement: Burkitt lymphoma
* a gene c-myc is located at the end of chrom 18q
* a gene promotor CH is located in the chrom 14q and it's a strong promoter for an immune response gene VH
* the q ends of chrom 14 and 18 swaps.
* c-myc gets a strong promoter and gets overexpressed.
32
genetic rearrangement: the Philadelphia chromosome
* the q ends of chrom 9 and 12 swap, resulting in chronic myelogenous leukimia (CML)
* in CML, WBCs are over-produced.
33
carcinogens: intrinsic factors
* genome
* hormone: cancer induction, growth, metastasis, supression, etc.
* notable influence in breast, prostate, endometrium and thyroid cancers
* viruses
* parasites: bladder cancer
34
carcinogens: extrinsic factors
* physical: radiation (damage to DNA + incomplete or faulty repair)
* mechanical: trauma, burns, chronic irritation or inflammation
* chemical: coal tar, aflaxtoxin B1 (from molds on peanuts)
* environmental: smoking, pollution, smoked food, insecticides
* occupational: rubber, arsenic, asbestos, uranium miners, vinyl chloride monomer (hemangioendotheliosarcoma of liver)
* diet: high fat, low fiber, additives, cooking and preservation
35
mechanism of chemical carcinogenesis
* carcinogen \>\> proximate carcinogen \>\> ultimate carcinogen (electrophilic center damages DNA)
* the toxins are water insoluble and ER tries to solubilize it but in the process, makes it a carcinogen
* cellular anti-xenobiotic activities
* phase 1: cytochromes: hydroxylation makes the compound more "conjugatable"
* phase 2: detox enzymes try to conjugate compounds into more inactive compounds that are easier to excrete.
* intestinal bacteria
* release of carcinogenic aglycones, nitrosamines, steroid metabolites and amino acid metabolites.
36
chemopreventive agents
* blocking agents
* prevent carcinogen activation
* enhance detox of carcinogens
* suppressing agents
* act after attack by carcinogens but prevents carcinogenesis
37
iatrogenic (physician-induced) causes of cancer
* IM injection of iron: sarcoma
* DES during preganacy leading to vagina cancer in daughters
* oral contraceptives: no increase
38
neoplastic progression
* multiple factors act together (mutations + carcinogens)
* persistent neoplasia increases risk of tumor and cancer
* as tomors and cancers grow, they develop new characteristics
* epigenetic changes: global hypomethylation of DNA with selective promoter-specific hypermethylation
* progression of tumor occurs independently in different tumors in the same organism or tissue
* etiologic factors may no longer be present when tumor develops
39
neoplastic promoters
* if promoters are introduced before carcinogen, the carcinogens are more likely to lead to tumor and cancer
* if promoters are introduced after carcinogen, no effect
* promoters themselves are not carcinogen
* phorbol esters (croton oil) for skin cancer
* phenobarbital for liver
* bile acids for colon
40
precancerous lesions
* familial polyposis of colon
* neurofibromatosis
* leuoplakia
* actinic keratosis
* atrophic gastritis
* chronic cell proliferation or atrohpy of any kind
41
metastasis
distal spread by lymphatics, blood vessels, or body cavities (Krukenberg tumor)
42
invasion of cancer cells
* cancer cells invade by attaching to the basement membrane and releasing enzymes that can breakdown the basement membrane
* normal cells can attach to base.memb but no enzymes to break it down
* cancer cells then enter blood vessels, lymphatics or body cavities and travel
* some cancer cells have receptors that can attach more easily to certain organs
* breast cancer to bones
* colon to liver thru portal
43
clonality and subclones
clonality: uniform cell population
subclones: due to new mutations, cells from a clonal development obtains new characteristics and become defferent from each other.
they differentiate by changes in epigenetics, genetic mutations or genetic rearrangements
differentiated cells may die, keep dividing or stop dividing and become quiescent
cancer therapy mostly focuses on proliferating cells and it's hard to target non-dividing cells
44
"cancer step cell" aka "tumor-initiating cell"
a cell which is analogous to the normal stem or progenitor cell but with dysregulated self-renewal mechanisms.
Vit A or DMSO can differentiate a stem-like cells into neutrophil-like cells
Vit D or TPA can differentiaet a stem-like cells into monocyte-like cells
malignant cells may be induced to differentiate into less-malignant cells
45
malignant tumor overview
usually derived from a single cell: clonal expansion
evolve in several stages
acquire new surface properties
loose dependence on growth factors
chromosomal abnormalities in most cells (gets worse as tumor gets advanced)
46
cancer mechanisms
* mitotic aberrations leading to loss or gain of chroms. \>\>\>immortal anueploid cells
* loss of domains from within chromosomes
* abnormal DNA repair genes
* tendency to gene amplification
* even normal cells can amplify gene expression without mutation (i.e., immune reponse genes in case of infection)
47
defense against cancer
repair enzymes that fixes DNA and cellular damages
immne response to abnormal cells
other factors limit the invasion of cancer cells outside of the original location
