Sarsour- Cancer Biology

Question 1

Define tumors

Answer 1

Space occupying lesions that may or may not be neoplasms

Question 2

Define neoplasm

Answer 2

Relatively autonomous abnormal growth with abnormal gene regulation (benign & malignant)

Question 3

Define cancer

Answer 3

Malignant neoplasm

Question 4

Define metastasis

Answer 4

Secondary growth of cancer at different location from primary neoplasm

Question 5

What are the 3 steps of carcinogenesis?

Answer 5

Initiation- simple mutation in one+ genes that control key regulatory pathways of cell
Promotion- selective function enhancement of signal transduction pathways that were induced by initiator by continuous exposure
Progression- continuing change of basically unstable karyotype

Question 6

Describe the first step of carcinogenesis?

Answer 6

Initiation: Irreversible, no threshold, genotoxic agents (chemicals, radiation, ROS, viruses). Sequence change in cellular DNA. can be result of activation of oncogenes or inactivation of tumor suppressing genes

Question 7

Describe the second step of carcinogenesis?

Answer 7

Promotion- long period of time, ReVERSIBLE in early stages, threshold exists, involves gene activation of repression such that the latent phenotype of the initiated cell becomes expressed thru cellular selection & CLONAL EXPANSION

Question 8

Describe the final step of carcinogenesis?

Answer 8

Progression- further complex genetic changes, irreversible changes in gene expression, evolution of karyotypic instability, selection for optimal growth in response to cell environment, converts benign tumors into malignant neoplasms

Question 9

Define oncogenes

Answer 9

Stimulate cell division/growth. Loss of regulation of gene expression can lead to enhanced expression of these proteins which causes unregulated cell growth
Activated by mutations/over expression in carcinogenesis. “Dominant” in their action. They result from a gain of function mutation

Question 10

Define tumor suppressors

Answer 10

Serve to check or inhibit cell division. Recessive. Loss of expression of these proteins leads to cell growth
Normal activity: repress growth
Carcinogenesis: inactivating mutations, deletions, loss of expression

Question 11

What 3 forms are oncogenes found in?

Answer 11

Cellular proto-oncogenes that have been captured by retroviruses
Virus-specific genes that behave like cellular proto-oncogenes that have been mutated
Cellular proto-oncogenes that have been mutated
When a mutation or rearrangement event is involved, it is said that the proto-oncogene has been activated

Question 12

Define the tumor microenvironment

Answer 12

The tissue environment in which cancer cells exists, that include normal cells, secretory factors, & extracellular matrix. Acts as a barrier for therapy, paracrine signaling, desmoplastic rxn, promotes tumor progression, therapy resistance, & recurrence

Question 13

What are the molecular features of breast cancer?

Answer 13

Activation of human epidermal growth factor receptor 2 (HER2)
Activation of hormone receptors (estrogen receptor & progesterone receptor)
BRCA mutation

Question 14

Explain the estrogen receptor signaling pathway

Answer 14

Breast cancer cells have relatively high ERa expression & low ERb expression. These receptors form homo or heterodimers upon ligand binding & translocate into the cell nucleus for transcriptional regulation, which is the main function of ERs. ER dimers bind to ERE region of target genes & recruit co-regulators to achieve regulation of transcriptional activity. They can also act as co-regulators for other transcription

Question 15

How does pancreatic cancer occur?

Answer 15

K-ras mutation is believed to be an early genetic event, followed by loss of functional p53, p16, SMAD4, and others

Question 16

What are the different mechanisms of cell death?

Answer 16

Type 1: Apoptosis
Type II: Autophagy (self-destruction)
Type III: Necrosis (explosive disaster)
Mitotic catastrophe
Senescence (irreversible growth arrest- reproductive cell death)

Question 17

What is necrosis morphologically characterized by?

Answer 17

Cell membrane swelling and rupture, cytoplasm: increased vaculoation, organelle degeneration, mitochondrial swelling, nucleus: clumping & random degradation of nuclear chromatin & DNA (karyolysis)

Question 18

What are the biochemical features of necrosis?

Answer 18

Inflammation, all cell types involved, extensive failure of normal physiological pathways that are essential for maintaining cellular homeostasis

Question 19

What are the two key players of necrosis that target the mitochondria?

Answer 19

Receptor-interacting protein 1 (RIP1)

Poly [ADP-ribose] polymerase 1 (PARP-1)

Question 20

What are the mechanisms of necrosis?

Answer 20

Ca2+ overload, mitochondrial uncoupling, increased O2 consumption, excessive ROS production, ATP depletion, no caspases involved

Question 21

What is apoptosis morphologically characterized by?

Answer 21

Cell membrane- membrane blebbing & eventually fragmentation into membrane-bound apoptotic bodies
Cytoplasm: fragmentation & shrinkage
Nucleus: chromatin condensation & degradation via specific DNA cleavage leading to nuclear fragmentation

Question 22

What are the biochemical features of apoptosis?

Answer 22

No inflammation, hematopoietuc cells & their malignant counterparts. Cell membrane will lose its asymmetry & phosphatidylserine becomes exposed on the cell surface (eat me signal). Caspase (protease)/mitochondria-dependent

Question 23

What are the 4 triggers of apoptosis?

Answer 23

1. DNA damage (ATM, p53)
2. Death receptors signaling (CD95, Fas receptor, TNF receptor superfamily, Caspase-8 mediated
3. Cell membranes (activation sphinogomyelinase & leading to hydrolysis of sphinogomyelin to ceramide)
4. Mitochondrial damage (Ceramide-mediated process, mitochondrial ceramide synthase activation)

Question 24

What key players are involved in autophagy?

Answer 24

Autophagy-related genes (proteins) (Atg)
Coiled-coil myosin-like BCL2 interacting protein (Beclin-1)(Atg6)-initiation of the formation of the autophagosome (nucleation)
Microtubule associated protein 1A/1B- light chain 3 (LC3)-conjugation & elongation

Question 25

What are the mechanisms of autophagy?

Answer 25

1. Release of Beclin from Bcl-2 which is then free to form Class III PI3K that contributes to formation of the nucleation complex
2. 2 independent conjugation cascades, the LC3-II & Atg5-12 cascades, serve to elongate the nucleation complex to generate limiting membrane
3. Sole transmembrane atg, Atg9, delivers additional membranes for limiting membrane formation
4. Limiting membrane then sequesters cytosolic cargo & seals upon itself to form an autophagosome
5. Fusion of autophagosomes to lysosomes results in cargo degradation & release of nutrients into cytosol

Question 26

Define mitotic catastrophe

Answer 26

Type of cell death that is caused by abberant mitosis

Mainly associated with deficiencies in cell cycle checkpoints

Question 27

What is mitotic catastrophe morphologically characterized by?

Answer 27

No change in cell membrane, larger cytoplasm w/formation of giant cell, micronucleation/multinucleation, nuclear fragmentation

Question 28

What are the mechanisms for induction of mitotic catastrophe?

Answer 28

1. Defects cell cycle checkpoints (p53- G2 checkpoint. BUB-related kinase- spindle checkpt. increased expression of multiple mitotic checkpoint genes- spindle assembly)
2. Hyperamplification of centrosomes- usually in subsequent cell cycle- CDK2/cyclin E/A (S-phase)
3. Caspase 2 activation during delayed apoptosis

Question 29

What is senescence?

Answer 29

Permanent cell cycle arrest, reproductive death
Can be a replicative senescence related to telomere shortening
Anti-transformation mechanism due to cellular damage

Question 30

Does senescence cause inflammation?

Answer 30

Yes but it is induced by secretory factors from the senescent cell itself

Question 31

What are the two pathways of senescence?

Answer 31

p53-p21
P16-Rb
Both yield same fate

Question 32

What are the two major examples of immune therapy in cancer?

Answer 32

Adoptive T cell therapy (CARs bypass MHC restriction & direct cytotoxicity to a target molecule on surface of malignant cell)
Personalized recombinant cancer vaccines (Neoantigens which are gene variants that encode peptides that are specific to the tumor are given in form of vaccines)