Chap. 24 Problem 1
The difference between a benign tumor and a
malignant one mostly involves the latter's
ability to invade and metastasize to other
tissues. Benign tumors create pathologies only
if they overexpress a hormone, etc. that
disrupts normal metabolism, or physically
interfere with tissue function due to their
size. Malignant tumors commonly posses most if
not all of the properties shown in Fig. 24.1.
From a mutational standpoint, malignant colon
carcinomas contain loss-of-function mutations
in the APC gene as well as cancer promoting
mutations in genes such as K-ras and p53. In
contrast benign colon polyps possess only lossof-function mutations in APC (Fig. 24.8).
Chap. 24 Problem 3
Malignant tumor cells secrete basic fibroblast growth factor (ßFGF),
transforming growth factor  (TGF, & vascular endothelial growth factor
(VEGF) to recruit blood vessels for delivery of oxygen and nutrients to
tumors. Tumors with their own vasculature can grow to a large size (Fig.
24.2a).
Chap. 24 Problem 6
The "multi-hit" model for cancer
induction theorizes that metastatic
tumor cells evolve from an original
transformed cell via the accumulation
of multiple mutations that increase its
survivability and invasion potential. The
multiple mutation theory is supported
by the fact that the incidence of
contracting most cancers increases
steadily with age (Fig. 24.6). The
multi-hit hypothesis also is supported
by studies of the transformation of
benign colon polyps into malignant colon
carcinomas and by other research.
Chap. 24 Problem 7
Genes that control cell growth and
proliferation are commonly mutated in cancers
(Fig. 24.11). Gain-of-function mutations that
increase the activity of growth-promoting
signaling molecules (I), receptors (II),
intracellular signal transduction pathways
(III), or TFs (IV) are associated with
cancers. These genes are referred to as
proto-oncogenes. Commonly, only a single
copy of the the gene needs to be altered.
Loss-of-function mutations in tumor-suppressor genes such as cell cycle
control proteins (V), DNA repair proteins (VI), or anti-proliferative factor
receptors such as the TGFß receptor can cause cancer. Usually both copies of
these genes need to be mutated. Lastly, gain-of-function mutations in antiapoptotic genes and loss-of-function mutations in pro-apoptotic genes (VII)
are associated with cancer.
Based on the above considerations, ras, Bcl-2, MDM2, and jun are protooncogenes. p53 and p16 are tumor-suppressor genes.
Chap. 24 Problem 10
About 10% of human cancers have a
hereditary basis. In most cases, the patient
inherits one non-functional copy of a tumorsuppressor gene. Cancer is induced after
the second functional copy of the gene is
inactivated by mutation (loss of
heterozygosity). Mutations in additional
genes typically also are required. The
induction of hereditary vs sporadic
(spontaneous) retinoblastoma, which involves
the RB gene, is compared in Fig. 24.13.
The hereditary form of this cancer usually
appears in childhood in both eyes. The
sporadic form (which requires two somatic
mutations) occurs later in life, and in only
one eye. Hereditary retinoblastoma exhibits
an autosomal dominant pattern of
inheritance due to the fact that individuals
with one mutant copy of RB have an
increased probability of developing the
disease.
Chap. 24 Problem 11
The concept of loss of heterozygosity
(LOH) is explained in the preceding
slide. In general, cells containing a
predisposing loss-of-function mutation
in one copy of a tumor suppressor gene
are normal until a mutation inactivates
the wild-type copy of the gene.
Cancer cells commonly exhibit LOH in
one or more tumor suppressor genes.
As illustrated in Fig. 24.14a, nondisjunction (mis-segregation) events
can result in LOH. Mutations that
affect genes required for quality
control at the spindle assembly
checkpoint commonly are observed in
cancers. This leads to nondisjunction
events and LOH of tumor suppressor
genes. Cancer cells commonly are
aneuploid (contain aberrant numbers of
chromosomes).
Chap. 24 Problem 12
After binding to hormones, growth factor RTKs
such as the EGF receptor autophosphorylate
themselves on cytosolic tyrosine residues.
Phosphotyrosines then recruit proteins of signal
transduction pathways to the receptor,
activating signaling. Cytokine receptors are
phosphorylated on cytoplasmic tyrosines by JAK
kinases, leading to activation of signaling. (a)
The viral protein gp55 binds to the
erthropoietin receptor, activating JAK kinases
in the absence of erythropoietin (Fig. 24.18).
This leads to erythroleukemia. (b) In the Her2
receptor, the substitution of glutamine for
valine in the transmembrane region of the
receptor causes dimerization and activation of
this growth factor receptor (Fig. 24.17). The
resulting protein is known as the Neu
oncoprotein, and is associated with some
breast cancers.
Chap. 24 Problem 13
Ras signals via the MAP kinase pathway that is coupled to growth factor
receptors. NF-1 (neurofibromatosis) is a GAP protein that catalyses GTP
hydrolysis on Ras. Gain-of-function mutations in Ras increase signaling, whereas
loss-of-function mutations in NF-1 activate signaling. Because only one copy of
a gain-of-function mutation is needed to activate a process, mutations in Ras
are more common than mutations in NF-1 in cancers. The first non-viral
oncoprotein discovered was RasD. In RasD, amino acid substitutions at glycine12 inhibit the GTPase activity of Ras keeping it locked in an active form.
Constitutively activated RasD proteins occur in many bladder, colon, mammary,
skin, and lung cancers, and in leukemias.
Chap. 24 Problem 14
The first oncoprotein discovered was
the v-Src viral tyrosine kinase derived
from c-Src (Fig. 24.19). c-Src is a
member of a family of cytosolic
tyrosine kinases implicated in cancers.
In v-Src, the C-terminal 18 amino
acids are deleted, including tyrosine527. Phosphorylation on this tyrosine
inactivates the wild-type c-Src
protein. Because this regulatory site is
missing from v-Src, the protein is
constitutively active.
Chap. 24 Problem 15
Often growth-promoting TFs or signal
transduction proteins are switched on by
translocation of their genes to regions of
the genome where they are highly
expressed. In Burkitt's lymphoma, a
translocation between the long arms of
chromosomes 8 and 14 places the c-myc
gene under the control of the enhancer
for the antibody heavy chain gene (CH)
(Fig. 24.22). This mutation is only
associated with lymphomas because the
antibody heavy chain gene is only
expressed in B-lymphocytes. DNA
containing a proto-oncogene can be
amplified, leading to over-expression of
the transforming gene product. The
latter is illustrated in Fig. 24.12a for
the N-myc oncogene. Staining shows that
N-myc DNA in one copy of chromosome
4 is greatly amplified in human
neuroblastoma cells. This type of
mutation is not limited to lymphomas.
Chap. 24 Problem 16
TGFß is an anti-proliferative factor that
signals via the Smad4 signal transduction
pathway in cells such as pancreatic cells
(Fig. 24.23). Loss-of-function mutations
in Smad4 result in decreased expression of
genes that limit cell proliferation. For
example, the p15 gene is a tumorsuppressor gene that encodes an inhibitor
of G1 cyclin-CDKs. p15 thus is important
for slowing cell proliferation. The PAI-1
gene encodes an inhibitor of plasminogen
activator. Plasmin degrades the
extracellular matrix. The loss of the
expression of these genes and other
TGFß-controlled genes contributes to cell
transformation.