Cancer Genetics Exam Two

immune system and cancer

innate and adaptive systems activated, over time cancer cells not eliminated develop mutations that make them invisible

Immuno-surveillance is

elimination. cells detected by innate and adaptive immune response. precancerous neoplasia eliminated mediated by NK cells 

Innate Immunity

expression of different cell surface markers including MHC class 1, engages cell death

adaptive immunity

more specific and long lasting, activates T and B lymphocytes which can differenciate into memory cells to help fight off similar cells in the future

immunoselection is

equilibrium. cancer cells gain mutations that make them invisible to the immune system. these cells can become dormant but remain alive for later reactivation. other tumor cells eliminated by the immune system improves growth environment for dormant cells

immunosubversion is 

escape. dormant cells revive and begin to grow accumulating mutations that directly affect function of immune response

apoptosis

cell suicide mediated by protein degrading enzymes called caspases. causes membrane blebs and fragmentation. eliminates unwanted or damaged cells

apoptosis signals from outside the cell

activation of receptors, injury of the cell membrane

apoptosis signals from inside the cell

direct mitochondrial injury, irreparable injury of DNA

what controls pro apoptotic molecules from exiting mitochondria

BCL2, BAX heterodimers

pro apoptotic elements activate—-

caspases that cleave and cause death/dismemberment 

Functional Changes 3 catagories

protein function, protein localization, protein stabilization

control of protein phosphorylation

ligand binding results in dimerization of RTKs, they phosphorylate each other and leads to activation of cell tyrosine kinases

receptor internalization and turnover signals control duration

membrane bubble, clatherin pit, degrades the receptor to the amino acid level so that the pieces can be used again. 

receptor activation—- first step in growth control 

activates pathways bound to phosphate domain, ultimate expression of RAS, pro cancer outcomes 

RAS signaling controlled by regulatory proteins

ras has inherently low abilities to bind to GTP (on) and to hydrolyze GTP (off). guanine exchange factors help bind GTP (SOS), and GTPase activating proteins help hydrolyze GTP (NF1)

mutant NF1

autosomal dominant disorder that results in benign tumor formation in nerve cells. highly potent, variable expressivity

RAS activation leads to kinase cascade 

RAS-RAF—→ activates MEK which activates ERKS 

what do ERKS do

activate proteins involved in translation and transcription.

C-myc levels controlled by

amount of beta catenin. WNT complex has to be bound to APC/AXIN complex to keep it active

phosphorylation of c-myc

leads to stabilization and increased transcriptional activity. done by ERKS

mutations that drive the cell to develop cancer

driver mutations

mutations that don’t contribute to the evolution of the tumor are called

passenger mutations

metastasis involves 

cancer cells entering the blood/lymph system

essential first step angiogenesis

penetration, transport, exit

original tumor is monoclonal but

increased mutation rate and genomic instability leads to a heterogenous population

inefficiency of metastasis due to 

intracellular and extracellular pathways. 

development of primary tumor: aggressive phenotype

oncogenic mutations, genomic instability

development of primary tumor: Prerequisites

self-renewal, invasiveness, motility, detachment, survival

development of primary tumor: microenvironment

angiogenesis, inflammation, cancerized stroma

Circulatory system: intravasation

epithelial to mesenchymal transitions

Circulatory system: Life in Transit

platelet association, embolism, vascular adhesion

why are epithelial to mesenchymal transitions important

gives carcinomas the ability to enter bloodstream more easily

Circulatory system: Life in Transit

platelet association, embolism, vascular adhesion

why is vascular adhesion, embolism (cell ball) and platelet association important

protects cells from shearing, vascular adhesion provides safe haven

Circulatory system: Distant accomplices

certain cell types encourage tumor growth and metastasis. Cancerized stroma: cells changed by cancer cells that help them grow

two examples of cancerized stroma

cancer associated fibroblast produces CXCL12, Tumor associated macrophage produces VEGF

Circulatory system: Homing

attachment, physical entrapment, attraction to survival signals/ligand receptor binding

Homing to bone

bone metabolizing factors released by tumor cells, tumor growth factors released in response

homing to lung

expression of chemokine receptor CXCR4 on tumor cells, expression of chemokine CXCL12 ligand in lung cells

homing to brain

breakdown of blood-barrier by tumor cells. interaction of tumor cells with neuronal cells

Finding a home: extraversion

promoted by VEGF which disrupts endothelial cell junctions. Motility, vascular remodeling

Finding a home: micro metastasis

tumors often become dormant once in tissue. will “wake up” in response to coopted stroma. metastatic site may already be preconditioned by the primary tumor.

BRCA-1

involved in DNA repair, one mutant allele in inherited breast cancer

what protein signals contact inhibition

HIPPO

gatekeeper example

APC mutations allow for more beta catenin

caretaker example

p53 controls cell cycle and dna repair

landscaper

SMAD4 
regulator of development and tissue homeostasis