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ASU Spring 2024 > BIO 302 - Exam 1 - Hallmarks of Cancer PowerPoint > Flashcards

BIO 302 - Exam 1 - Hallmarks of Cancer PowerPoint Flashcards

1
Q

What are the Hallmarks of Cancer?

A

Ability to evade immune system
Ability to invade and metastasize
Deregulation of cellular energetics (metabolism)
Evading growth suppression
Genomic instability and mutation

Induction of new blood supply (angiogenesis)
Limitless replicative potential
Resistance to cell death
Sustaining proliferative signaling

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2
Q

Cancer cells

A
  1. Activate or de-activate normal cell behaviors in inappropriate ways
  2. Flip biological switches inappropriately
  3. Ignore or bypass normal control mechanisms
  4. Utilize normal biological mechanisms in abnormal ways
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3
Q

How do these Hallmark biological capabilities successfully develop?

A

Proliferative signaling
Activation of cell migration
Angiogenesis
Programmed cell death
Evasion of immune system

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4
Q

Cell division is a ______ ______ process to ensure homeostasis (equilibrium).Normal (stem) cells ___ ___ divide unless…

A

tightly regulated / do not / they receive an “on” signal (a growth factor docks on a receptor on their surface)

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5
Q

How do cancer cells exhibit a loss of proliferation control?

A

Sustained proliferative signaling
Evasion of growth suppression

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6
Q

Three types of cell proliferation and activation

A
  1. Autocrine (own cell)
  2. Paracrine (neighboring cell)
  3. Endocrine (distant cell)
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7
Q

Generic Signaling Pathway: All elements are proteins from proto-oncogenes.

A
  1. Growth Factor: Signal Initiation
  2. Growth Factor Receptor:
    Transmission of Signal into the Cell
  3. Signaling Pathway Relay Proteins:
  4. Transmission of Transcription Factors in Nucleus:
    Response = Cell Division or Other Gene Activation
    Signal to Nucleus
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8
Q

What are the 5 mechanisms of sustained growth signaling?

A
  1. Point mutation - Abnormal hyperactive protein.
  2. Gene amplification - Excess normal protein.
  3. Chromosomal translocation - Abnormal & Excess.
  4. Local DNA arrangement - Insertion, deletion or inversion / transposition.
  5. Insertional mutagenesis - Viral DNA & excess normal protein.
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9
Q

Translocation causes cancer in two ways

A
  1. Formation of an oncogene fusion protein (an abnormal protein).
  2. Proto-oncogene activation by a new promoter (over-production of normal protein).
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10
Q

______ is the primary cause of most blood cancers.

A

Translocation

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11
Q

It’s estimated that translocations are present in up to ______ of ______ and over ______ of ______.

A

90% / lymphomas / 50% / leukemias

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12
Q

Translocations are also found in adult solid tumors such as…

A

Prostate, breast, thyroid and kidney carcinomas and some sarcomas.

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13
Q

In contrast to adult cancers, pediatric cancers have very low mutational rates but are driven by?

A

chromosomal rearrangements (fusion genes)

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14
Q

What is the Philadelphia Chromosome?

A

Translocation (biomarker) that involves chromosome 9 and 22. Chromic in every case of Chronic myelogenous Leukemia and frequent in Acute myelogenous Leukemia.

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15
Q

Gene amplification and oncoprotein over-production as a target for therapy

Breast Cancer:
What does ompanion diagnostic immunohistochemistry test measures?
Only patients with cancers that have _______________________ get the (life-saving) targeted therapy.

A

over-abundant protein from over-expressed genes

3+ protein or 2+ protein with gene amplification by FISH testing

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16
Q

Mutation creates loss of _______ _______ ______.

A

negative feedback function

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17
Q

Evading Growth Suppressors

Pro- and anti-mitosis signals are coordinated in normal cells.

What is the cell cycle?
What are the checkpoints?

A

Cell cycle = the series of events that occur during cell division.
“Checkpoints” in the cell cycle are “stop points” that halt progression and are controlled by proteins from tumor suppressor genes.
Stop defective cells from multiplying

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18
Q

Cancer cells de-activate “stop” signals for proliferation through:

A
  1. Mutating tumor suppressor genes (leading to loss of function).
  2. Deleting tumor suppressor genes all together.
  3. Silencing expression of tumor suppressor genes through epigenetics.
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19
Q

What are Histone deacetylases (HDACs)?

A

Histone deacetylases (HDACs) are enzymes that allow histones to wrap DNA more tightly.

HDACs are overexpressed or overactive in many cancers.

Tumor suppressor genes are “silenced” by this mechanism.

Unwound: DNA available for transcription
Wound up: No “reading” of genes

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20
Q

What are the two Classes of Tumor Suppressor Genes?

A

Gatekeepers
Act through cell cycle to stop cell proliferation
Loss of function mutations lead to excessive proliferation
Example: p53

Caretakers
Function in DNA repair and chromosome sorting
Includes “spell checkers” that repair normally-occurring replication errors (i.e., DNA polymerase errors)
An error normally occurs once per every 10 billion base pairs
Loss-of-function mutations contribute to genomic instability
Examples: BRCA1, MLH1

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21
Q

What are the nuclear tumor suppressor genes?

What happens if they are mutated?

A

Nuclear tumor suppressor genes: BRCA1 and BRCA-2 DNA repair genes
If BRCA1 or BRCA2 is mutated, damaged DNA is not repaired properly

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22
Q

The cell cycle: asymmetric cell division

Checkpoint control proteins prevent the cell cycle from preceding when one of the following problems is present:

A
  1. DNA has been damaged (altered) and needs repair.
  2. Spindle assembly is incorrect and cannot support normal chromosome attachment and segregation.
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23
Q

Checkpoint control Involves tumor suppressor genes, including…

A

p53 (master tumor suppressor gene)

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24
Q

Single most commonly mutated gene in cancer

A

TP53 - Caretaker gene activation

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25
Q

What causes excessive activation, driving the cell cycle forward?

What causes loss of inhibition of the cell cycle, allowing it to proceed without control?

A

Overexpression of cyclin-dependent kinases (CDKs) and cyclins (oncogenes) resulting from mutational events.

Downregulation and/or mutation of inhibitors (tumor suppressor genes).

26
Q

What transition is defective in 80-90% of cancers?

A

G1 –> S

27
Q

”The _________ is actually a vast collection of many genome.

Each subclone acquires unique mutations as progression continues over time

Increasing ______ of the cancer genome occurs as newly acquired mutations further compromise and/or knock out the “repair or die” controls of tumor suppressor genes.

A

” genome of a cancer” / heterogeneity

28
Q

What are the 5 cellular stresses on the road to cell death?

A

DNA damage
Immune response

Metabolic stress
Mitotic failure

Telomere shortening

29
Q

What are the 6 cellular responses to cellular stressors?

A

Apoptosis
Autophagic cell death
Cell cycle arrest

Mitotic catastrophe
Necrosis
Senescence

30
Q

Mutations affecting apoptosis can contribute to the development of diseases.

A

TOO MUCH
Alzheimer’s
Parkinson’s
Huntington’s disease
Stroke
AIDS

TOO LITTLE
Cancer

31
Q

Apoptosis is initiated either from:

A

Inside the cell (cell stress): Intrinsic pathway

Outside the cell (binding and activation of death receptors): Extrinsic pathway

Anoikis is the phenomenon that if the cytoskeleton is detached from the basement membrane, it dies.

32
Q

The death signal is propagated through a signaling pathway by multiple caspase proteins (enzymes), activated in series, to enzymes that dissolve the cell when activated.

A

Initiators: relay enzymes that activate downstream caspases

Effectors: enzymes that break down cell constituents

33
Q

Both positive and negative controls exist in BCL-2 gene family

A

Bcl-2 (inhibit caspases – negative control)
Bax (activate caspases – positive control)

34
Q
A

IAPs: Inhibitors of apoptosis protein family (negative control)

35
Q

The outcome of apoptosis is?

A

Breakdown of the cell components
Formation of a dense cell corpse or multiple cell fragments

36
Q

Different STMULI Activate Pathway to Death

A

Stimulus:
INTRINSIC: DNA damage, Lack of O2, Internal cell damage

EXTRINSIC: Ligation of death receptors (Fas, TNF, TRAIL),
Growth factor withdrawal

ANOIKIS: Loss of extracellular matrix contact

Initiation: Initiator caspaces activated &
Mitochondria involved in internal pathway

Effector Caspases: Effector (digestive) caspaces activated

Execution: Cascade of irreversible protein degradation
Cell dismantled

37
Q

What 3 ways does cancer escape apoptosis?

A

Cancer cells can down-regulate Fas on their cell surface.
Cancer cells can down-regulate production of caspaces.

Cancer cells can increase levels of intracellular inhibitory proteins.

38
Q

NK = natural killer cells are part of the ______ ______ ______.

CD8 = cytotoxic “killer” T cell are part of the ______ ______ ______.

A

innate immune system / adaptive immune system

39
Q

What are the Implications of mutations in the Apoptotic Pathways?

A
  1. Prevents the elimination of cells with damaged DNA or mutations within the cell cycle.
  2. Enables tumor survival in an abnormal environment and in circulation (anoikis becomes irrelevant).
  3. Causes resistance to therapy because apoptosis in response to chemotherapy-induced DNA and other cell damage is averted.
40
Q

What is the Hay flick limit?

A

“Hayflick limit”: normal human fibroblasts will undergo only about 40-60 cell divisions in a Petri dish (Hayflick and Moorhead,1961.)
Even when provided appropriate nutrients and growth factors, normal cells reach a point when they stop dividing, and become permanently senescent.

41
Q

Cannot replicate telomeric DNA at ends of chromosomes without the enzyme ______, a highly specialized reverse transcriptase.

A

telomerase

42
Q

Telomerase and Cancer (Slide 54)

A
43
Q

How does therapeutic inhibition of telomerase leads to upregulation of ALT pathway?

A
44
Q

Alternate Lengthening of Telomeres (ALT)

A

10-15 % of cancer cells use this pathway to lengthen telomeres (usually the cancers that are the most difficult to treat: brain, lung cancer; sarcoma)

ALT is unique to cancers and cell lines but uses normal DNA repair mechanisms in abnormal ways

Involves copying telomeric sequences by homologous recombination (nucleotide sequence exchange) with other telomeric DNA

45
Q

Describe cellular metabolism (Slide 57)

A
46
Q

What is the Warburg Hypothesis?

A

Otto Warburg discovered that tumors consume tremendous amounts of glucose relative to most non-transformed tissues, and that the majority of glucose consumed by tumors is fermented to lactate, rather than oxidized in pathways that require respiration.

Aberrant metabolism in cancer cells
Preferential use of anaerobic metabolism, even in the presence of oxygen

More glycolysis, more lactate production

47
Q

Why create more glycolysis?

A

Glycolysis and other metabolic pathways increase nucleotide, amino acid, and lipid synthesis
More building blocks for more cells!

Lactate is an autocrine growth factor for cancer cells.

Lactate stimulates normal cells in the cancer micro environment to secrete growth factors that, in turn, support cancer cells.

Loss of energy production compensated by dramatic increase in glucose uptake: cancers are sugar junkies

48
Q

Glucose uptake

A

Basis for a clinical imaging test for cancer
Glucose transporter 1 (GLUT1) facilitates glucose uptake by cells.
Increased expression in many cancers
Other glucose transporters too
GLUT1 upregulated by oncogenes (e.g., c-Myc)
Normal p53 inhibits GLUT1

49
Q

Cancer heterogeneity: Some tumors can have two populations of cells:

A
  1. One that uses glucose and through glycolysis secretes lactate
  2. Another that uses lactate as an energy source in oxidative phosphorylation
50
Q

Angiogenic Switch (Slide 67)

A

Key factors: vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) - Highly expressed in many cancers.

51
Q

What are the characteristics of tumor vasculature?
What are the three things tumor vasculature is known for?

A

Poorly organized, chaotic and leaky.

Increases infiltration of inflammatory mediators
Facilitates invasion and metastasis
Impairs drug delivery

52
Q

Hypoxia gradient in cancer masses

What elements decrease as therapy resistance increases?

A

Drug conc.
Cell cycle
Nutrition
pO2

53
Q

> 90% of all cancer deaths due to?

A

DISTANT metastatic disease

54
Q

Epithelial to Mesenchymal Transition (EMT) is characterized by what 6 things?

A
  1. Loss of molecular anchors between cells.
  2. Loss of organization of epithelial cell layers
  3. Altered cell-cell adhesion
  4. Loss of basal membrane attachment
  5. Degradation of the basal membrane
  6. Acquired motility
55
Q

Epithelial to Mesenchymal Transition (EMT)

A
  1. Allows an epithelial cell to assume a mesenchymal cell phenotype
  2. Results in enhanced migratory capacity, invasiveness
  3. Completes when underlying basement membrane is degraded and the mesenchymal cell can migrate away from the epithelial layer
56
Q

MET allows cancer cells to?

A

Attach and anchor to their new site.

57
Q

New properties a cancer must acquire to successfully metastasize:

A
  1. Survival in the primary tumor
  2. Invasion of surrounding tissue
  3. Epithelial-mesenchymal transition (loss of requirement for fixed contact to neighboring cells and underlying matrix)
  4. Evasion of destruction by host immune defenses
  5. Intravasation (entering a vessel)
  6. Survival in the circulation
  7. Extravasation (exiting a vessel)
  8. Mesenchymal-epithelial transition
  9. Survival in a new environment

ALL capabilities are required.
Most cancer cells don’t succeed.

58
Q

What are the mesenchymal cells in and around the tumor contribute to its “success?”

A

BDMC
Blood Vessel
Endothelial cell
Epithelial cell
Fibroblast
Invasive tumor cell
Lymphatic endothelial cell
Lymphocyte

Macrophage
Mast cell
MDSC
MSC
Neutrophil
Pericyte
TEM

59
Q

What are the molecules that cancer cells use to manipulate the microenvironment?

What do they stimulate?

A

Cytokines, chemokines, proteases

Increase in Angiogenesis, EMT, Survival & Metastasis

60
Q

Tumor-associated macrophages (TAMs) are attracted by ______ ______ and stimulated to secrete ______ _______ for the cancer. Other cells also contribute through ______ ______.

A

cancer cells / growth factors / paracrine stimulation

ASU Spring 2024 (10 decks)

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