Additional Concepts and Review Flashcards
carcinogenesis is stepwise
several mutations required for malignancy
mutations are acquired 1 at a time- change in growth potential and phenotype
many gene targets
multistage concepts
initation- unrepaired DNA alteratoins caused by carcinogen that undergo at least 1 cyvcle of proliferation and become fixed in a cell line
promotion- stimulates clonal expansion of initiated cells- cells are still dependent on normal pathways for growth
progression- reflects additional genetic and phenotypic changes required for malignancy (angiogenesis, no basement membrane, telomerase, apoptosis evasion)
hall marks of cancer
self sufficiency in growth signals insensitivity to growth inhibitory signals altered cellular metabolism evasion of apoptosis limitless replicative potential angiogenesis invasion and metastasis evasion of immune response genome instability inflammation
inflammation in cancer
generation of promutagenic ROS causes increased turnover d/t parenchymal regeneration
ex helicobacter pylori, hepatitis C
HPV
e7 binds to Rb
e6 binds to p53
stop apoptosis and feed forward cell cycle
immune surveillance
normal function of the immunesystem to scan the body for emerging malignant cells
evidence: spontaneous regression lymphocytic infiltrates in tumors increased cancer in immunocompromised presence of tumor specific t cells and Abs in cancer pts more cancers in aged individuals
immunoediting
ability of the immune system to shape and mold the immunogenic properties of tumor cells that leads to selction of subclones that evade immune response
tumor Ags
abnormal proteins
over expressed or aberrantly expressed proteins
viral Ags- HTLV, EBV, HPV
oncofetal Ags- AFP (hepatomas), CEA (GI, breast)
altered cell surface glycolipids/proteins- CA-125, CA-19-9 ovarian carcinomas, MUC1- ovarian and breast carcinomas
cell type specific differentation Ags- normally present on cells of origin, but ilicit response when over expressed
ex. CD20- expressed by b cells and lymphoma
recognition of cancer
cell mediated dominates
NK cells attack with no MHC1- no sensitization required. may also kill following opsonization
T cell- MHC 2
b cells- used more w/ therapeutic
immune evasion
passive- decreased MHC expression, immunoediting, Ag loss
active- immune suppressoin
imunoregulatory activation- PDL1, PDL2
secretion of immunosupressive factors- TGF-B
induction of regulator T cells
PDL1
program death ligand 1 is on tumor cells and binds PD1 on T-cells, inactivating them
tumors upregulate PDL1, decreasing cellular death
thus, PDL1 antibodies can block this method of immune evasion
tumor microenvironment
tumors create an environment in which normal cells are co opted to “help” tumor cells
