24: Cell Cycle, Cell Death, And Cancer Flashcards
Five phases of the cell cycle and what occurs in each
- G0: quiescent
- G1: first gap phase
- S: DNA replication
- G2: second gap phase for growth
- Mitosis
(First four = interphase)
Four phases of mitosis
Prophase: chromosomes condense into sister chromatids, attach to the mitotic spindle
Metaphase: sister chromatids line up at the equator attached to opposite poles of spindle
Anaphase: sister chromatids become daughter chromosomes and are pulled to opposite poles of the spindle
Telophase: spindle disassembles, chromosomes packaged into separate nuclei, cytokinesis
Three checkpoints in cell division and what happens in them
- START: G1 to S: cell commits to cell cycle entry
- G2/M: chromosome alignment on spindle
- M: triggers anaphase and cytokinesis
What tumor suppressor plays a role in checkpoint 1 of cell cycle?
P16
What CKI plays a role in G1 phase of interphase?
p21
Four examples of CKI
P16, p21, p27, CDC25
Five examples of oncogenes
EGF, Ras, Myc, cyclins, ATM
Four examples of tumor suppressor genes
P53, Rb, p14ARF, p16INK4A
Activity and level of CDKs and cyclins throughout cell cycle
CDKs: levels constant, activity changes
cyclins: levels change, activity changes
Major DNA damage trigger of cell death
DSBs
Why is cell death considered a cell cycle event?
Activation of cell cycle checkpoints
3 initiation and 3 executioner caspases
Initiators: 8, 9, 10
Executioners: 3, 6, 7
Examples of BH3 family proteins
Bid, Bim, Bad, Noxa, Puma
Function of autophagy
Degradation of long-lived proteins and organelles
What causes mitotic catastrophe?
Cell cycle checkpoint deficiencies
Three fates of the cell that undergoes mitotic catastrophe
- Mitotic death right away
- Delayed cell death -> divide for many cycles before dying
- Senescence: exit mitosis and undergo permanent G1 arrest
Replicative senescence
Due to telomere shortening
Tumor
Space-occupying lesion - may/may not be neoplasm
Neoplasm
Relatively autonomous abnormal growth with abnormal gene regulation (benign or malignant)
Cancer in two words
Malignant neoplasm
Hallmarks of cancer
- Self sufficient
- Limitless replicative potential
- Insensitive to inhibitors
- Evade cell death and destruction
- Sustain angiogenesis
- Capability to invade and metastasize
- Create genome stability
- Promote inflammation
Three stages of carcinogenesis
Initiation, promotion, progression
Initiation of carcinogenesis
Genotoxic event causing mutation in 1+ gene that controls cell regulation (activation of oncogene or inactivation of tumor suppressor gene)
Promotion stage of carcinogenesis
Epigenetic event involving change in gene regulation
Is promotion in carcinogenesis irreversible? Is there a threshold?
It is reversible in early stages + threshold exists in time and dose (occurs over a long period of time)
Progression in carcinogenesis
Clastogenic events that further change karyotype / make it unstable
What does progression in carcinogenesis result in?
Conversion of benign tumor into malignant neoplasm
What is notable about inactivation vs methylation of Rb gene?
Different alterations to the gene cause different clinical results (retinoblastoma vs brain tumor vs osteosarcoma, etc.)
Three major cellular components of the tumor microenvironment
- Immune cells
- Fibroblasts and other stromal cells
- Blood vessel cells
Three major components of the tumor microenvironment
- Cellular components
- Secretory factors
- ECM
Secretory factors in the tumor microenvironment
Signaling molecules, GFs, inflammatory factors, enzymes
Four reasons the tumor microenvironment is important
- Barrier for therapy
- Paracrine signaling occurs here
- Desmoplastic reaction
- Can promote tumor progression
Fibroblast aging and cancer
Older fibroblasts may contribute to pancreatic cancer progression using ALOX12 and 12-HETE (inflammatory mediators) in the tumor microenvironment (Dr. Sarsour’s research)
Most frequent malignancy in women
Breast cancer
Three molecular features of breast cancer
- BRCA mutations
- HER2 activation
- Hormone receptor activation (estrogen and progesterone)
Most common exocrine pancreatic neoplasm
PDAC: pancreatic ducal adenocarcinoma
A typical early genetic event in pancreatic cancer
K-ras mutation
Four types of cancer therapy
- Surgery
- Radiation
- Chemotherapy
- Immune therapy
What cells are most affected by radiation
Cells with reproductive activity, long dividing future, and have the least fixed morphology and function
Two mechanisms of radiation therapy
- Direct energy deposition to break DNA bonds
2. Hydrolysis of water to produce free radicals
Five types of chemotherapy agents
Alkylating agents, intercalating agents, antimetabolites, mitostatic agents, platinum derivatives
Two types of immune therapy for cancer
- Adaptive T cell therapy
2. Personalized recombinant cancer vaccines
Adaptive T cell therapy
Isolated T cells from pt genetically modified to express CARs (ags) that can bypass MHC restriction -> cytotoxicity to target on surface of malignant cell
