Solid Tumor COPY Flashcards
Cell Cycle
- Gap 0 (G0): Rest phase
- Gap 1 phase (G1): cell growth and DNA preparation for synthesis
- produce RNA; required nitrogen supply + energy - S-phase (synthesis): DNA replication
- Gap 2 phase (G2): further cell growth + mitosis preparation
- assembly of microtubules; DNA assessed for damage (P53 immune suppressor) - M Phase (mitosis): inhibit microtubule function + block topoisomerase (DNA unwinding) FXN
Factor affecting multiple cycles
antitumor antibiotics
50% of cancers
- breast
- prostate
- colon
- lung
Neoplasms
- malignant
- benign
new growth
- unregulated growth of the cells, tissue invasion, and metasis (cancerous)
- lack ability to invade other tissues, little impact to overall health (benign)
Carcinogenesis: Initiation
normal cell exposed to carcinogens –> causes genetic alterations (but not subject to just genetic alterations, ie: epigenetic alterations) –> DNA damage repaired + reversed by cell regulation mechanisms; proliferation can be reversed by apoptosis
-progression = irreversible as mutations are promoted + mutated cells accumulate
CANCER: selective growth advantage, clonal populations develop –> MULTIPLE MUTATIONS required for cancer (exception: BCR.ABC chronic myelogenous leukemia)
Carcinogenesis: Initiation
- acquired
- inherited
- small cell lung cancer or Hodgkin lymphoma (Epstein Barr)
- BRCA 1/2 gene (ovarian risk, breast cancer in women) or Lynch syndrome (colon cancer, others)
Types of Mutations:
- point
- frameshift
- missense
- nonsense
- duplication
- mutation involving substitution of a single base pair
- insertion or deletion of 1 or 2 base pairs so that
- a mutation that results in a change in the amino acid
- a mutation that results in a premature signal to stop building a protein
- results in multiple copying
Common Initiation Mutations
–> activation of oncogenic pathways
-oncogenes: a gene that has the potential of causing cancer when activated
EX: growth factor receptors, proteins involved in cell cycle checkpoints
(EGFR, KRAS, ALK , BCL-ABL, others)
-EGFR mutation present in lungs and colon rectal cancers
–> inactivation of apoptotic pathways
-tumor suppressor genes
EX: receptors of inhibitory pathways, apoptotic proteins, mutations involving cell surface proteins
-P53 pathways: majority of cancers have mutations that affect p53
(APC, BRCA1, BRCA2)
- -> mutation repair pathways
- MMR: MLH1 in colorectal cancers
Carcinogenesis: Promotion
altered environment to allow growth of altered cell populations
- promoters: chemicals that stimulate activation and proliferation
- suppress the regulatory pathways/proteins
- activate the growth pathways - MITOGENIC: reversible, tumors may regress if stimuli removed
tumors are considered benign at this point
EX
- benign breast tumors
- polyps in colon
Carcinogenesis: Conversion/Progression
multiple mutations accumulate creating a favorable environment
- chromosomal abnormalities, gene amplification, recombinations.
interactions with the microenvironment
- inflammation, blunting of immune responses, angiogenesis
ultimately leading to progression of cancer
Progression from polyp to stage IV
cells become malignant depending on environment
antagonists:
- normal epithelium –> aberrant crypt foci: NSAIDS, folate, statins
- aberrant crypt foci –> small adenoma: NSAIDs, statins
- small adenoma–> large adenoma: NSAIDs, statins, AKT, EGFR inhibitors
promoters:
- aberrant crypt foci: COX-2 over expression
- aberrant crypt foci –> small adenoma: HMG-CoA R overexpression
- small adenoma–> large adenoma: caveolin-1, AKT over expression
Benzopyrene and Lung Cancer
carcinogen found in cigarette smoke
- binds to DNA forming a covalent adduct
- disrupts shape of DNA and alters transcription/translation –> transversion from a G:C base pair to A:T base pair
- CpG islands: G:C rich regions that shut down gene translation
prolonged exposure=additive effects
EGFR mutation and lung cancer
epidermal growth factor receptor (mutations result in gain of copy number)
- 10% of lung cancer = EGFR +; indolent course of lung cancer and sensitive to tyrosine kinase inhibitors
- develops resistants
Colon Cancer and promoters
familial adenomatous polyposis (FAP)
-MUTYH mutation: tumor suppressor gene
cancer risk increases exponentially by age; many polyps don’t result in cancer
-COX2 over expression; treated with chemoprohylaxis (CELECOXIB: COX2 inhibitor)
Estrogen and Breast Cancer
breast cancer is graded/treated on the following:
- presence of estrogen receptor/progesterone receptor
- human epidermal receptor-2 status
- BRCA status
estrogen=promoter
- overexpression of ER allows the cancer to respond to pro-growth signal; more ER = stronger response
adding anti estrogen or aromatase inhibitor can control breast cancer
- inhibitory molecules: without them it would result in proliferation
- aromatase inhibitors, tamoxifen
Luria and Delbruck
conducted experiment to understand how mutations arise in bacteria
result: number of resistant colonies varied significantly between plates
-resistance is due random mutations
cancer cells are no different: some are inherently resistant to a chemotherapy agent
Goldie-Coldman Hypothesis
probability of resistance to a drug is greater as the size of a tumor increases and.or the rate of division increases
principles:
- tumors need to show sensitivity to each agent as a single agent
- drugs used in combination should have different mechanisms of action
Inflammation and Cancer
immune system can recognize and eliminate cancerous cells –> cancer relies on inflammation and trick the immune system to survive
checkpoint pathways are essential for immune response:
- CTLA-4, PD-1, LAG-3, TIM-3
- in cancer, cells up regulate checkpoint pathways
Hodgkin’s lymphoma
Hodgkins cells turn up inflammation and turn off cytotoxic attacks on cancer cells
- NF-kB pathway, TNF-alpa pathways are unregulated
- inflammatory pathways recruit immune cells
PD-1 and PD-L1 Inhibition
PD-1 inhibitors:
nivolumab (opdivo) –> lung cancer
pembrolizumab (keytruda)
PD-L1 inhibitors:
atezolizumab (tecentriq)
durvalumab(imfinzi)
-normally protects against excessive immune system stimulation
Cancer Growth: Gompertzian growth
fraction of tumors progressing thru cell cycle influences susceptibility
- as time increases:
- cells develop chemo resistance
- competition over nutrients
- fewer cells going through division
Angiogenesis
development of new blood vessels
NORMALLY:
-induced by hypoxia–> damaged tissues will release pro-angiogenic factors into circulation (VEGF and PDGF)
CANCER:
- growth becomes dependent on nutrient supply:
- blood supply becomes rate limiting step
- cancers need blood and oxygen
Target for drug therapy
Metastases
As tumors get larger, cells are shed from tumor
- invasion of vasculature
- angiogenesis
- degrade and detach from extracellular matrix
Circulating tumor cells (CTC): measurable cells circulating in the vasculature
colonies establish, extravasate and grow; specific cancers metastasize to common sites
Staging of Cancer
staging utilizes a TNM description; staging does not direct therapy
stage 1: small tumor, local disease, goal:cure
stage 2: large tumor, local-regional disease, goal:cure
stage 3: small - large tumor, regional disease, goal: cure-palliation of symptoms
stage 4: small - large tumor, present metastasis, global disease, goal: palliation
