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Cancer- abnormal
cell growth (cell
growth not under
"normal" control)
Benign tumors
are self-limitinghave contact
inhibition
Malignant tumors
can metastasize
and induce
tumors in other
tissues 24-1,
1055
Cancer cells have high DNA:cytoplasm ratios,
several nucleoli in nucleus, and may have
abnormal numbers of chromosomes
Malignant cells less differentiated (cell fate less
determined) than benign cells
Benign tumors usually pose no threat except what
may be posed by their physical presence
Benign tumors can become malignant
24-6, 1060
Progression of
colon cancer
Cell culture –
some cells lose normal control of growth and proliferation in
culturechange in morphology, reduced need for growth factors,
substrate-loss of contact inhibition (keep moving and growing)
transformation or malignant transformation
cell strain-lasts about 50 divisions
cell line-immortal if continually fed and diluted
fibroblasts-"fibrous germinating cells"
normal
transformed
Cells can be transformed with radiation,
oncogenes, chemicals, and viruses
In addition to the characteristics just listed,
they
also…
>have increased mobility of integral membrane
proteins
phospholipid itself not more mobile-but instead
connections between protein and cytoskeleton
altered
>increased glucose transport (GLUT with lower Km
for glucose)
>reduced or absent fibronectin (protein that
forms meshwork over normal cells in culture)
>altered gene transcription -but only 3% of total
mRNAs unique to transformed state
Oncogenes encode proteins that can transform cells in
culture or cause cancer in animals
Proto-oncogenes are the "normal" copies of a gene,
that if mutated, will become oncogenes
src - the gene ("sarc")
Src - the protein that src
makes
7 classes of
proteins
that are coded
for by oncogenes
24-9, 1064
24-7, 1061
oncogenes work
cooperatively to
produce cancers
24-14-16, 1070-71
Activation of oncogenes-often
result in signal constantly “on”
A single mutation
(V for G) reduces
GTPase activity and
converts to
oncogene
p16-cyclin kinase inhibitor
Rb-inhibits E2F-transcription factor required for
synthesis of DNA replication machinery-(such as
DNA polymerase) 24-19, 1075
p53-arrests cells in G1 who have had significant
DNA damage
mutations in p53 show up in >50% of human cancers
p53 is a
tetramer-if
only one allele
is mutated,
messes up
nearly all
copies of
functional
protein
Other factors indirectly activate oncogenes
DNA viruses-viral DNA inserted specifically or at
random into genome
RNA viruses- random or specific integration-once
incorporated into genome called provirus-if
incorporated into genome can be passed to progeny
0.1-1% of total genome is proviral in mice
HIV, hepatitis B, papilloma, Epstein-Barr viruses all
can cause cancer in humans
Chemical
carcinogens
-activate
oncogenescan cause general
mutagenesis
-either directly
mutagenic or
become so after
being metabolized
phorbol esters-mimic DAG-constitutively active PKC
Aflatoxins- from mold on grains-potent mutagen
Other Cancer Tidbits…
epigenetic events may cause some cancers
>p16 present and not mutated, but heavily methylated
in many cancers
-Cancer and EMF link?
6 studies say yes, 9 no
EMF cause increase in calcium signaling, RNA
synthesis, gene expression, src kinase
No effect of DNA mutation, chromosomal
aberration, NO production, tumor promotion, DNA
synthesis, cell proliferation
11 of 13 studies attempting to repeat a previously
published effect failed
Breast Cancer
BRCA1, BRCA2 genes were thought to give high
probability of breast cancer if mutated
Now the correlation is breaking down
tamoxifen treatment in healthy women at high
risk reduces incidence of breast cancer by 45%
side effects of increased endometrial cancer
risk and blood clots (but only if you begin taking
it after 50)