Studied by 13 people
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neoplasia
new growth
because cancer is a genetic mutation, mutations that are passed onto daughter cells are subject to Darwinian selection
when will there be a cure for cancer?
mutations and epigenetic alteration impart to cancer cells a set of propoerties
what are cancer hallmarks?
benign neoplasm
growth that is localized to one place
malignant neoplasm
genetically altered growth that invades surrounding tissue
invade surrounding tissue and metastasize to a distant site
what are malignant tumors capable of doing?
cell must develop mutations that allow it to no longer obey boundaries of adjacent cells allowing for more uncontrolled growth
must have its own blood supply
how do cells become neoplastic?
cells must gain the ability to invade the basement membrane and surrounding tissue
enter the bloodstream
spread to grow within distant organs
what must cells have to become malignant neoplasms?
malignant cell growth
what is cancer a disease of?
less responsive nature of tumor cells to normal growth control mechanisms
what does autonomous growth describe?
malignant neoplasms interfere with the function of normal tissues
why is cancer fatal?
1. evading growth suppressors
2. sustaining proliferative signaling
3. avoiding immune destruction
4. enabling replicative immortality
5. tumor promoting inflammation
6. activating invasion and metastasis
7. inducting or accessing vasculature
8. genome instability and mutation
9. resisting cell death
10. deregulating cellular metabolism
what are the ten hallmarks of cancer that doctors look for?
unlocking phenotypic plasticity
non mutational epigenetic reprogramming
polymorphic microbiomes
senescent cells
what are the new emerging/enabling hallmarks?
manipulates telomeres to keep them from shortening and become immortal
how do cells enable replicative immortality?
aerobic glycolysis inhibiotrs
what is the therapeutic targeting agent to stop deregulating cellular energetics?
EGFR inhibitors
what is the therapeutic targeting agent to stop sustaining proliferative singlaing?
cyclin dependent kinase ihibitors
what is the therapeutic targeting agent to stop evading growth surpressors?
immune activating anti-CTLA4 mAb
what is the therapeutic targeting agent to stop avoiding immune destruction?
telomerase inhibitors
what is the therapeutic targeting agent to stop enabling replicative immortality?
selective anti-inflammatory drugs
what is the therapeutic targeting agent to stop tumor promoting inflammation?
inhibitors of HGF/c-Met
what is the therapeutic targeting agent to stop activating invasion and metastasis?
inhibitors of VEGF signaling
what is the therapeutic targeting agent to stop inducting angiogensis?
PARP inhibitors
what is the therapeutic targeting agent to stop genome instability and mutatioin?
proapoptotic BH3 mimetics
what is the therapeutic targeting agent to stop resisting cell death?
g1 phase
what period are cells responsive mitogenic GFs and TGF-beta?
proto-oncogenes
normal genes that have the potential to become oncogenes
mutations or amplification to become oncogenes
how do protooncogenes get altered?
oncogenes
cancer causing genes that encode for cancer-causing oncoproteins
hyperactive and less responsive to growth control mechanisms
how do oncogenes act in cancer?
tumor suppressor
genes or anti-oncogenes that encode tumor suppressor proteins that inhibit cell division
p53, Rb, transforming growth factor beta (TGF-B)
what are the three tumor suppressors?
in cancer which is what increases the risk
when are tumor suppressor gene functions lost?
entrance into M phase blocked if DNA replication is not completed
what is the checkpoint for G2 phase into M phase?
anaphase blocked if chromatids are not properly assembled on mitotic spindle
what is the checkpoint in the M phase from metaphase to anaphase?
entrance into S phase is blocked if genome is damaged
what is the DNA checkpoint from G1 phase into S phase?
DNA replication halted if genome is damaged
what is the DNA damage checkpoint from S phase into G2 phase?
binds to DNA and activates other genes that help repair damage or trigger apoptosis (programmed cell death) if the damage is irreparable
how is p53 a tumor suppressor?
inhibits cell growth and promotes apoptosis
how is transforming growth factor beta (TGF-b) a tumor suppressor?
DNA binding protein that regulates transcription of S phase genes
how does Rb acts act a tumor suppressor?
it is lost
what happens to tumor suppressor function in cancer?
pleomorphism
variations in size, shape, stianing, organelles, mitotic figures, etc among cells of a single species
mitotic figures
condensed chromosomes seen during mitosis
they will divide more
what is an irregularity in mitotic figures that contribute to pleomorphism?
how much or how little tumor tissue looks like the normal tissue it came from
what is differentiation of cancer cells?
when malignant cells regain control of their growth and stop behaving like cancer cells by reverting to their nonmalignant state
what is tumor reversion?
cervical cells are scraped, placed on a slide, and stained
what happens in a pap smear?
low nuclear-to-cytoplasmic ratio and light staining nuclei
what do normal cervical squamous cells look like?
dysplastic cells
pre-cancerous cells that are abnormally formed, but not malignant
high nuclear to cytoplasmic ratio
abnormally shaped nuclei
darker stained nuclei indicating more DNA synthesis
what are the characteristics of dysplastic cells?
amount of space occupied by the nucleus in relationship to the space occupied by the cytoplasm
what is a nuclear-to-cytoplasmic ratio?
a sign of cellular atypia or malignancy
what does a high nuclear-to-cytoplasmic ratio indicate?
culturability
normal human cells do not grow well in culture, cancer cells grow easily and can be transplanted to other hosts
loss of contact inhibition, failure to mature, immortal lifespan
what are the three reasons that cancer cells can be transplanted to other hosts?
dysplasia
term used to describe presence of abnormal cells within a tissue or organ
no but it could become it
is dysplasia cancer?
hyperplasia and dysplasia
what do cells undergo before becoming cancer cells?
increase in the number of cells in an organ or tissue that appear normal under a microscope
what occurs in hyperplasia?
normal cells -> hyperplasia -> dysplasia -> cancer
what is the progression of cells from normal to cancer cells?
loss of organization and increase in disorganization
what happens to the organization of cells when it goes through hyperplasia and dysplasia?
reversible
are hyperplasia and dysplasia reversible or irreversible?
1. initiation
2. hyperplasia/dysplasia/intraepithelial neoplasia
3. invasion through the basement membrane
what are the three steps of normal to malignant tissue?
cell acquires a mutation in a cancer related gene but still appears normal
what happens in the initiation step of normal to malignant tissue?
initiated cell has proliferated more than neighboring cells, basement membrane intact
what happens in the hyperplasia/dysplasia step of normal to malignant tissue?
bening noninvasive nesoplasm
what is formed from step two of the normal to malignant tissue formation?
invasive, malignant cancer
what type of cancer does an invasion of the basement membrane become?
membrane is not intact and it is invasive
what does invasive carcinoma membrane look like?
membrane is intact and there is no cancer
what does high-grade intraepithelial neoplasia membrane look like?
not sufficiently differentiated to produce hormones
produce substances that are usually only produced during embryonic development
autocrine and paracrine growth factor production
revert to more primitive pathways
what are the signs that a cell has biochemical deviations that could lead to cancer?
tumor specific antigens (CD10)
what are the signs that a cell has antigenic deviations that could lead to cancer?
proteins or other molecules that are found only on cancer cells and not on healthy cells
what are tumor specific antigens?
looking for tumor specific antigens (CD10)
what can be useful in diagnosing cancer?
non lethal genetic damage where multiple genes are altered
what are the signs that a cell has genetic deviations that could lead to cancer?
mutations
amplifications
chromosomal translocations
aneuploidy (abnormal chromosome number)
what are the types of genetic alterations that could cause cancer?
missense
nonsense
frameshift
insertions
deletions
what are the types of genetic mutations?
multiple copies of the same gene
what could amplification cause in the genes?
abnormal chromosome number
what could aneuploidy cause in a gene?
activation of oncogenes due to breaking of chromosome
loss of tumor suppressor genes
loss of DNA repair genes
what are the consequences of genetic damage?
greater susceptibility to more mutations and breaking DNA
what can loss of DNA repair genes cause?
from a single cell as a result of a single initiating genetic mutation
what does a tumor arise from?
tumor contain one common genetic mutation and genetic heterogeneity
what is the result of tumors mutating and having different cells with different mutations?
multiple genetic changes that occur over many years
what can malignant cancer result from in terms of tumor heterogeneity?
protein loses its ability to effectively regulate cell growth and division, leading to uncontrolled cell proliferation and increased risk of cancer development
what happens to the p53 gene when it is mutated?
translocation
change to a chromosome in which a fragment of one chromosome attaches to a nonhomologous chromosome
philadelphia chromosome
what does translocation of chromosome 9 and 22 cause?
leukemia
what does philadelphia chromosome cause?
lymphoma and leukemia
what does translocation of chromosome 8 and 14 cause?
more invasive cancer
what does more mutations in a cell cause?
result of mutations in genes that encode components of signaling pathways downstream of growth factor receptors
how do cancer cells acquire growth autonomy?
RAS and ABL
what are the two oncoproteins that act as signaling molecules?
control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation
what does RAS control?
ligand binding activity to growth factor receptors cause downstream signaling proteins to activate their nuclear targets and signals are transmitted to the nucleus through various signal transduction molecules
how does downstream signal transducing proteins work?
RAS
what is the most commonly mutated oncogene in human tumors?
30%
what percent of human tumors contain mutated RAS genes?
mutations in amino acid residues that are either within GTP binding pocket or the enzymatic region that carries out GTP hydrolysis
how is RAS commonly activated?
stimulates downstream regulators of proliferation by several interconnect pathways that converge in the nucleus and alter expression of genes that regulate growth
how does activated RAS affected growth?
- trametinib
- cobimetinib
- binimetinib
what are the MEK inhibitors?
a fraction
how effective are MEK inhibitors?
enzymes that are involved in the development and progression of human cancers
what is the function of MEK?
drugs that block the activity of MEK1 and MEK2 proteins that regulate cell growth and survival
what are MEK inhibitors for?
help keep cancer cells from growing and may kill them
why is MEK inhibition important?
Note 
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