Lecture 10: Cancer 1 Flashcards
cancer is a group of diseases in which cells develop malignant properties and become
- aggressive
- invasive
- metastatic
tumor
mad of abnormal growth of tissue, can be benign or malignant
neoplasia
formation of presence of new, abnormal growth
neoformation
new growth in reference to a tumor
malignancy
cells that are
- aggressive
- invasive
- metastatic
bening tumors
self-limitind in their growth and do not invade or metastasize
(not aggressive, invasive, or metastatic)
carcinoma
tissue of origin: epithelial tissue
sarcoma
tissue of origin: bone, cartilage, muscle, fat, connective tissue
leukemia
tissue of origin: bone marrow
lymphoma
tissue of origin: immune system
cns cancer
tissue of origin: brain and spinal cord
melanoma
tissue of origin: melanocytes
probability of being diagnosed with cancer
40%
probability of dying of cancer
20%
most common cancer types
- prostate
- lung
- breast
- colon, rectum
-pancreas (not that many cases but out of those cases majority die)
probability of being diagnosed and dying of a cancer in the oral cavity and pharynx
diagnosed –> 1%
dying–> 0.3%
carcinogenesis
- the accumulation of growth promoting mutation that results in cell transformation
- occurs in already existing (somatic cells) –> not passed down
mechanisms of carcinogenesis
- spontaneous gene or chromosome mutations
- mutagens or radiation
- tumor viruses (RNA and DNA)
- inherited predisposition; “cancer families”
RNA tumor viruses
RNA tumor viruses (oncogenic retroviruses) contain viral oncogenes derived from cellular proto-oncogenes capable of transforming cells
DNA tumor viruses
- human papilloma virus (HPV) causes cervical cancer, oral caner
- epstein-barr virus (herpes 4) causes burkitt’s lymphoma or nasopharyngeal cancer
- human herpes virus 8 causes kaposi’s sarcoma
DNA tumor viruses
- human papilloma virus (HPV) causes cervical cancer, oral caner
- epstein-barr virus (herpes 4) causes burkitt’s lymphoma or nasopharyngeal cancer
- human herpes virus 8 causes kaposi’s sarcoma
genes that are mutated in cancer
- proto-oncogenes
- tumor suppressor genes
- mutator genes
proto-oncogenes
- gain of function mutations: covert proto-oncogenes to oncogenes (“activates them”)
- heterozygous
- ex: point mutations, deletions, gene amplification, chromosomal translocation
- genetic signature: limited number of mutations–> they are “drugable” (good targets for drug therapy)
tumor suppressor genes
- loss of function mutations: tumor suppressor genes result in cell transformation
- homozygous
- genetic signature: large number of mutation–> potential target for gene therapy
mutator genes
- loss of function mutations in enzymes involved in DNA replications and repair
- enhance that rate of mutation accumulation
- homozygous
receptor tyrosine kinase signaling leads to
the activation of a transcription factors affecting growth and proliferation
steps in receptor tyrosine kinase signaling
step 1: activation of receptor tyrosine kinase
step2: activation of KRAS
step3: activation of BRAF
general structure of the receptor tyrosine kinase
- extracellular domain (variable–> to recognize different ligands)
- little transmembrane domain
- intracellular domain which is a tyrosine kinase (phosphorylates other proteins on tyrosine residues)
step 1: what happens when the ligand binds to the extracellular portion?
you get a dimerization, then they cross phosphorylate each other
mutational events that activate EGFR
activating point mutations or deletions cause ligand independent dimerization (activate receptor) –> lead to epidermal growth factor receptors over expression
epidermal growth factor receptor tyrosine kinase inhibitors
- iressa: orally active EGFR tyrosine kinase inhibitor
- traceva: used in lung and pancreatic cancer
- caprelsa: used in medullary thyroid cancer
step 2: activation of KRAS
- once you activate the receptor the next step is KRAS
- KRAS is not an enzyme (not easily inhibited)
- small GTP binding protein (active when bound to GTP)
- bound to the membrane
KRAS mutations
if you have these mutations you can get stuck in the active form of KRAS (pathways keeps going)
- almost always caused by the same type of mutation on codon 12 or 13
- 20% of all tumors have a RAS mutation
farnesyl trasnferase (FTase)
enzyme that helps in the anchoring of KRAS to the cell membrane
inhibiting this enzyme would inhibit KRAS
step 3: activation of BRAF
RAS bind to and activates BRAF
- BRAF is an enzyme which means there are powerful inhibitors for this step
- mutations in the kinase domain, V600E is a common kinase activator
BRAF mutations in which cancers
-melanoma
-colorectal carcinoma
papillary thyroid carcinoma
-some rare brain tumors
philadelphia chromosome
- a piece of chromosome 9 switches with a piece of chromosome 22
- the new and shorter chromosome 22 contains abnormal BRC-Ab1 gene fusion
- found in chronic myelogenous leukemia (CML) (95% carry this translocation)
- gleevec is an effective treatment because it inhibits abnormal tyrosine kinase
these lead to photo-oncogenes being converted to oncogenes
Activation of receptor tyrosine kinases (EGFR)
KRAS activation
BRAF activation
Philadelphia chromosome - BCR-Abl tyrosine kinase
