Cancer 2a Flashcards
1
Q
Cancer
A
uncontrolled proliferation of cells that serves no physiologic fxn
2
Q
neoplasm
A
any new growth
3
Q
benign
A
encapsulated and well-differentiated
4
Q
malignant
A
invasive and dedifferentiated
5
Q
tumor
A
reserved for malignant cancers
6
Q
metastasis
A
spread of cancer to other areas of the body-est. of secondary tumors
7
Q
tumor marker
A
specific biochem marker (hormone, enzyme,gene,antibody) present in or on tumor cells, or in body fluids
8
Q
Benign cells charcteristics
A
-grow slowly
-well-defined border
-not invasive
-well-differentiated: looks like cells which they arose from
-dividing cells are rare
-does not metastasize
9
Q
Malignant cells characteristic
A
-grow rapidly
-does not have a border
-invade local structure and tissues
-poorly differentiated, may not be able to determine tissue or origin
-many dividing cells
-can spread distantly through blood and lymph vessels
10
Q
Normal cells
A
-differentiate
-follow specific instructions
-fulfill roles of cell type
-populations controlled by balance of apoptosis and growth
11
Q
Cancer cells
A
-break all the rules
-dedifferentiate: cells lose organization and order
-become anaplastic (without form) and pleiomorphic (many shapes, sizes)
-no longer fulfill specified role
-hijack the body’s mechanisms to promote their own survival.
12
Q
Hallmarks of cancer cells (8 biological capabilities)
A
- sustaining proliferative signaling
- evading growth suppressors
- Enabling replicative immortality
- Resisting cell death
- Inducing and accessing vasculature
- activating invasion and metastasis
- avoiding immune destruction
- deregulating cell metabolism
13
Q
Hallmarks of cancer cells -2 enablers of change
A
- Genome instability and mutation
- Tumor-promoting inflammation
14
Q
Mutations characteristics
A
-5-6 different pathways are required to transform normal cells to cancer cells
-accumulate with age
15
Q
Genetic changes (mutations)
A
-DNA changes
-Epigenetic changes
-microRNA expression
16
Q
Types of genes prone to mutations
A
-oncogenes
-tumor suppressor genes
-caretaker genes
17
Q
Point mutation
A
change of single nucleotide
18
Q
nucleotide insertions/deletion
A
changes way that the gene is “read”
-think adding a random letter to a word
19
Q
chromosomal rearrangement
A
may lead to the production of new or altered protein
20
Q
gene amplification
A
increases copy number of genes and hence gene effects
21
Q
gene silencing
A
turns off a gene’s effect
22
Q
exogenous sequence
A
from virus, can alter fxn
23
Q
Oncogenes
A
normally signal proliferation-signal cell to divide
-common ex. RAS
24
Q
RAS
A
a “molecular switch” that initiates proliferation
-point mutation turn the switch on permanently
25
Chronic myeloid leukemia (CML)
result of novel protein that promotes uncontrolled growth
26
Chromosomal translocation
2 chromosomes fuse together in the middle of 2 different genes
ex. bcr on chromosome 9
abl on chromosome 22
resulting protein --> promotes myeloid cell proliferation
27
N-myc
-a normal oncogene
-fetal brain development
-( in neurblastma cells?)
28
Gene amplification
leads to hundreds of copies of
gene-->exaggerated proliferation signal
29
Tumor-suppressor genes
normally halt proliferation- tell the cell to stop dividing
-mutation makes these genes inactive.
30
Tumor-suppressor gene types
-RB1(retinoblastoma)
-p53
-APC
-BRCA1 (breast cancer)
31
requires ___mutation because we have __alleles for each gene
2, 2
32
RB1 (retinoblastoma gene)
-normally strongly inhibits division
-inactivation leads to uncontrolled proliferation (point mutation)
-requires 2 mutations to inactivate both copies of genes
33
p53 gene
-normally guardian of the genome
-activated by cell stress
-when a cell is damages, p53 tells it to repair or die.
-mutated p53 gene found in nearly every human cancer ever studied
-activated caretaker gene
34
Caretaker genes
-normally maintain genomic integrity
-conducts DNA repair; repair mismatched not, signal-strand breaks, dbl-strand breaks.
-mistakes during replication or exposure to radiation/chemicals
-loss of fxn leads to incr mutation rates
-MANY of the genes implicated in cancer
35
epigenetic changes
-alter expression of genes without mutating sequence
36
Meythlation
addition of methyl molecules to DNA blocks transcription
-STOP signal-no transcription
-DNA can be directly methylated, silencing tumor-suppressor genes or activation oncogenes
37
methylation of _____promotes cancer
tumor suppressor genes
38
demethylation of _____ promotes cancer
oncogene
39
Acetylation
-allows gene expression
-alters histones and chromatin
-GO signal
40
microRNA (miRNA)
-short sequences 22 nt that bind to mRNA
-Inhibiting translation into protein
-changes in miRNA abundance can change expression of genes
41
Oncomirs
miRNAs that stimulate progression of cancer
42
1. Sustaining proliferative signaling
-induced angiogenesis
-lots of proliferation =lots of blood flow and nutrients needed
-tumor cells release growth factors
43
Growth factors
released by tumor cells:
-Vascular endothelial growth factor (VEGF)
-Platelet-derived growth factor (PDGF)
-Basic fibroblast growth factor (bFGF)
44
2. Evading growth suppression
-contact inhibition
-anchorage dependence
-due to loss of cadherin and integrin expression
45
Contact inhibition
- in normal stop dividing after forming a complete monolayer bc of contact
-in cancer cells that will keep dividing and pile on each other
46
Anchorage dependence
-Non-cancerous cells only proliferate when attached to a surface. they cannot divide in soft agar bc they cannot attach
-cancer cells are anchorage-independent can proliferate in soft agar
47
telomeres
-are repeated sequences at the ends of chromosomes
-maintain chromosome stability during replication
-normal cells can only divide a finite amount of times --> Hayflick limit-->senescence (stops dividing)
48
Telemore shortening is prevented in stem cells bc of
an enzyme, telomerase
49
3. Enabling replicative immortality
-telomers
-cancer stem cells regain the ability to synthesize telomerase. and avoid senescence
50
4. Resisting cell death
-apoptosis normally triggered when cell is stressed/damaged
-able to survive repeated cycles of DNA damage, metabolic stress, hypoxie etc.
51
cancers cells resisting cell death
decrease pro-apoptotic signals-p53
increase anti-apoptotic signals-bc12
52
metastasis
distal spread of cancer cells, usually through blood and lymph vessels
53
metastasis steps
1. invasion
2. detachment and intravasation
3. survival in circulation ( difficult)
4. extravasation
5. colonizing distal site
54
1. invasion
local spread of cancer cells
-recruitment of macrophages to primary tumor (TAMs)
-promoting local angiogenesis for nutrient supply
-changes in cell adhesion molecule expression to make cancer cells more mobile-->incr mobility
55
2. detachment and intravasation
-secretion of enzymes that digest extracellular matrix (ECM)-Matrix metalloproteinases (MMPs)
-free cancer cells from stoma
-cancer cells that have undergone epithelial-mesenchymal transition (EMT) are most likely to succeed with this step.
-cancer cells infiltrate local blood vessels
56
3. survival in circulation
-normal cells undergo apoptosis when detached from ECM (anchorage-dependence)
-cancer cells, especially those that have undergone EMT, are resistant to this
-avoid detection by immune cells by attaching to circulation platlets
-very few cancer cells with service circulation (v stressful)
57
4. extravasation
-cancer cells in circulation often stop in narrow vessels or at branch points
58
metastases tends to show up in
-liver
-lungs
-brain
-bone
59
5. colonizing distal site
-colonizing a distal site requires an environment that favors the cell's growth (tumor niche)
-not all cancer cells that arrive at a distal site will survive long enough to form a secondary tumor
60
7. avoiding immune destruction
-tumors produce/secrete cytokines and chemokines that attract macrophages to site
-co-opt macrophages to promote health rather than inflammation
61
THE macrophages THT promote health rather than inflammation:
-TAMs (tumor-associated macrophages)
-anti-inflamm effects
-block actions of t cytotoxic cells
-secrete GFs for local tissue remodeling, angiogenesis
-secrete (MMPs) that degrade ECM
62
T-reg cells
-predominant lymphocyte
-normally active in wound healing to prevent damage of healthy tissue
-secrete high levels of IL-10
-manipulated in cancer to prevent damage of healthy tissue
63
tumors ____ pro-inflammatory signals and ____ anti-inflamm effects. which allows for __-
-suppress, promote
- tumor to expand unimpeded by immune response
64
8. deregulating cell metabolism
metobolic stress
warburg effect:
-despite presence of O2 cancer cells primarily use glycolysis
-many mutations associated with cancer support metabolic shift
65
glycolysis
-lactate broken down to produce produce building blocks for cells
66
epithelial cells
mature and differentiated
67
mesenchymal cells
types of progenitor cell (stem cell)
-not many in adults (kids have more)
-you will see these cells in wound healing
-you will see this in cancer -cell from epithelial to mesenchymal
68
Epithelial-mesenchymal transition (EMT)
-occurs in embryonic development
-wound healing/tissue remodeling
-cancer
69
most cancers develop in _____
epithelial tissue
70
EMT
external signals-->activate transcription factors-->change gene expression and cell behavior
71
EMT makes cells more stem like through:
-few adhesion molecules
-no polarity
-able to redifferentiate
-resistance to apoptosis
-unlimited replicative potential
72
EMT Transition driven by cytokine and chemokines of ____
tumor microenvironment
73
Tumor growth is enhanced by interaction between cells and local environment:
-induced angiogenesis (autocrine signaling)
-Monocytes/macrophages converted to TAMs
-Immune response hijacked to support tumor growth
-appearance of cancer stem cells
74
TAMs
tumor-associated macrophages
75
cancer stem cells
-cells within tumor are NOT homogenous; mixed populations that may contain cancer cells acting as stem cells
--(this is why cancer treatments are multifaceted)
76
stem cells have the ability to
-form new growths
-may explain recurrence of tumors after treatment
77
Tumor niche
-idea that certain organs are more inviting for metastases
-aka "seed and soil"-hypothesis that's some organs are more fertile for metastases to thrive
78
cancer cells change the environment for their benefit through____
-recruiting immune cells (TAMs and T reg cells)
-secrete their own growth factors (angiogenesis and tissue remodeling)
79
Adenoma
a benign neoplasm derived from glandular cells
80
Carcinoma
malignant neoplasm derived from epithelial cells
81
Sarcoma
malignant neoplasm derived from mesenchymal cells (fat, muscle)
82
Lymphoma
malignant neoplasm derived from lymphocytes
83
Melanoma
malignant neoplasm derived from melanocytes
84
Germ cell tumor
malignant neoplasm derived from germ cells
85
What causes the mutations to lead to cancer?
-mutagen, carcinogen
86
Mutagen
-any substance that has potential to cause genetic alteration
-increase risk for cancer but don't necessarily cause it
87
Carcinogen
any substance that contributes to cancer progression
-a type of mutagen
88
examples of carcinogens
-workplace exposure (industrial chemicals, paint, solvents)
-environmental (UV tradition, some bacteria, viruses)
-residential (asbestos, processed meat)
89
Viral carcinogens
-viruses can lead to cancer directly or indirectly
-human papilloma virus
-Hep B or C
90
human papilloma virus
-Direct
-Can be anal, cervical, oropharyngeal)
-virus incorporates its own DNA into host's cells (stratified epithelium)
-Viral protein (E6) shuts of p53: cell damage w/o apoptosis
-E7 forces cell cycle into replication
91
Hepatitis B or C (liver)
-indirect
-Cytotoxicity--> chronic inflammation, oxidative stress, tissue damage
-programming damage mutates cells
92
Bacterial carcinogens
Helicobacter pylori
93
Helicobacter pylori
-80% have bacteria in stomach (asymptomatic)
-10-20% chance of developing stomach ulcers
-1-2% risk of developing stomach cancer
-uses flagella to burrow through mucus layer
-->infect gastric epithelial cells
94
H. Pylori possible mechanisms for causing cancer
-enhanced free radical production increases rate of mutations
-induces local inflammatory response (high levels of TNF-alpha and IL-6) leading to metaplasia of gastric epithelium
95
Inherited carcinogens
-breast and ovarian
-non-polyposis colorectal cancers
-li-Fraumeni syndrome
96
Breast and ovarian cancer syndrome
-BRCA1 and BCRA2
-also attributed to fallopian cancers, breast cancer in men
97
Hereditary non-polyposis colorectal cancers
-involves DNA repair genes
-also endometrial, ovarian, pancreatic, small intestine, stomach, kidney cancers
98
Li-Fraumeni syndrome
-mutated p53
-can cause sarcoma, leukemia, and brain, breast,adrenal cortex cancers
99
Where do tumor markers detect cancer?
blood, urine, CSF
100
Tumor marker uses:
-to screen and identify those at high risk for cancer
-to diagnose specific type of tumor
-to follow clinical course of tumor
101
Prostrate tumors- tumor marker:
-prostrate specific antigen (PSA)
102
Liver cell tumors-tumor marker
alpha-fetoprotein (AFP)a
103
Adrenal medulla tumor-tumor marker
catecholamines (epinephrine)
104
Limitations of tumor markers
-false positives are possible
-cancer is heterogeneous-makes different markers prominent in diff ppl
-many cancers don't have identified markers (high research priority)
105
Cancer treatments
-sx removal
-radiotherapy
-chemotherapy
-immunotherapy (active or passive)
-hormonal therapy
-targeted therapy
106
Chemotherapy agents
-cytotoxic agents
-take advantage of specific vulnerabilities of cancer cells
-poorly tolerated, can damage healthy cells
-combo of chemo agents typically used bc tumors are heterogenous
107
chemo different classes of drugs
have different targets:
-cell growth pathways
-DNA replication
-microtubule structure
108
Chemotherapy agents
-alkylating agents
-nitrosoureas
-anti-metabolites
-plant alkaloids
109
Alkylating agents
carboplatin, cisplatin
-target DNA, kills all replicating cells
110
Nitrosoureas
carmustine
-slow down DNA repair mechanisms
111
Anti-metabolites
methotrexate, flururacil
-interfere with DNA/RNA in dividing cells
112
Plant alkaloids
paclitaxel, vincristine
-anti-mitotics, prevent cells from entering cell division phase
113
Immunotherapy (active)
-direct immune system attack to cancer cells through id of (TAAs) tumor-associated antigens
-immune cells removed from pt
-genetically modified to recognize some tumor-specif marker
-cultured and returned to pt
"anti-cancer vaccine"
114
Immunotherapy (passive)
-not as direct as active
-enhancing natural anti-cancer mechanisms
-Tumor targeting antibodies
-cytokines
115
Tumor targeting antibodies
-bind tumor cell and initiate cell death or interfere with cells fxn
-can activate complement syeste, to initiate cell death or interfere with cells fxn
-cetuximab: targets EGFR treats head and neck cancers
-rituximab: activates complement system, treats leukemia and lymphoma
116
Cytokines
-used adjuvants to other therapies
-Interferons, interleukins
117
Hormonal therapy
-used for tumors in hormonal-responsive tissues
-don't directly kill cells-cut off their ability to respond to hormone signals
-Tamoxifen (breast): competes with substrate for ER, blocks proliferation
118
Aromatase inhibitors
-enzyme that converts androgens->estrogens
-block formations of estrogens "starve" dependent cancer
-useful in tumors resistant to tamoxifen
-anatroxole
119
Targeted therpy
-small molcule inhibitors that target specific proteins
-receptor kinase inhibitors:
-imatinib-binds to mutated protein to stop
-chronic myeloid leukemia (CML)
-competitively binds to bcr-abl fusion protein
-blocks substrate binding and thus cell proliferation
