Tumor suppressor genes 2

3p tumor suppressor genes
Allele loss in 3p, including LOH and homozygous
deletion, occurs in nearly 100%of SCLCs and more
than 90% of NSCLCs and is one of the earliest
events in lung cancer development. Because of the
early changes in chromosome region 3p21.3 (oc-
curring in histologically normal lung epithelium)
the presence of 3p allele loss and inactivation of
expression of these 3p TSGs can be of use in de-
termining smoking related field effects. Three dis-
creet regions of 3p loss have been identified by
allelotyping in lung cancers, including, a 600-kb
segment in 3p21.3, the 3p14.2 (FHIT/FRAB3), and
the 3p12 (ROBO1/DUTT1) regions. The 3p21.3 re-
gion has been analyzed most extensively and 25
genes were identified from this region.
One of the best studied genes in this region is
RASSF1A, which is rarely mutated in lung cancer
but whose expression is frequently lost by tumor
acquired promoter methylation [51,52]. RASSF1A
is involved in multiple pathways critical to can-
cer pathogenesis, including cell cycle, apoptosis,
and microtubule stability. RASSF1A is methylated
in ∼90% of SCLCs and ∼40% of NSCLCs and has
the ability to suppress the growth of lung cancer
cell lines in tissue culture and as xenografts in nude
mice [51,52].
FUS1 is located next to RASSF1A and one of the
two alleles of the gene is often lost in lung cancers.
FUS1 is rarelymutated in lung cancers, does not un-
dergo promoter hypermethylation, yet the protein
product of this gene is frequently lost in lung can-
cer compared to normal lung tissues [53].Wild-type
FUS1 but not tumor-acquiredmutant FUS1 induces
G1 growth arrest and apoptosis [53].Administration
of FUS1 with in DOTAP:cholesterol (DOTAP:Chol)
nanoparticles (FUS1-nanoperticles) inhibits cancercell growth in vitro and in vivo. These preclinical
studies provide a basis for FUS1 gene therapy clin-
ical trials for the treatment of lung tumors using
FUS1-nanoparticles [54,55].
Two other 3p21.3 candidate tumor suppressor
genes, Semaphorin 3B (SEMA3B) and a family
member SEMA3F, are extracellular secreted mem-
bers of the semaphorin family, and are impor-
tant in axonal guidance. Wild-type SEMA3B, but
not missense mutant SEMA3B, induces apopto-
sis when re-expressed in lung cancers or added
as a soluble molecule [56,57]. Overexpression of
SEMA3F in tissue culture results in inhibition of
tumor cell growth and tumor cell invasion. Both
SEMA3B and SEMA3F are soluble, secreted pro-
teins, and therefore are promising candidates for
drug development.
Two other 3p genes with evidence to support
their candidacy as tumor suppressors are FHIT and
retinoic acid receptor beta (RARβ). FHIT is located
in 3p14.2, one of the most common fragile sites of
the human genome. FHIT is either homozygously
deleted or expresses aberrant transcripts in more
than 50% of lung cancers [58]. In addition, FHIT
overexpression induces apoptosis in lung cancer
cells. RARβ is located at 3p24 and functions as a
receptor for retinoic acid (RA). Although the RARβ
gene is not mutated in lung cancer, it undergoes
methylation in 72% of SCLCs and 41% of NSCLCs,
leading to loss of its expression [59]. Re-expression
of RARβ in lung cancer cell lines suppresses their
growth in the culture and nude mice [60].
Oncogenes and the pathways
they regulate
While there are multiple components to each of the
growth signaling pathways involved in lung can-
cer, we will focus the discussion on those proteins
that are frequently affected by genetic abnormalities
in cancer. It has become clear that these mutated
proteins, while driving cells toward transformation,
also “addict” the cells to their abnormal function.
This concept is referred to as “oncogene addiction”
and represents a cellular physiologic statewhere thecontinued presence of the abnormal function,while
oncogenic, also becomes required for the tumor to
survive [61]. This means that if the function is re-
moved or inhibited, for example, by a targeted drug,
the tumor cells die. By contrast, bystander normal
cells, which are not “addicted” to the mutant pro-
tein, are much less sensitive to the drug; thus, the
targeted drugs have great tumor cell specificity. The
most important example of this concept for lung
cancer is EGFR. Tumors withmutations in EGFR are
dependent on survival signals transduced by mu-
tant EGFR, and thus are particularly sensitive to ty-
rosine kinase inhibitors (TKIs) [62]. These findings
have led to massive genome-wide sequencing ef-
forts (discussed above) targeting thousands of genes
to find additional mutated oncogene targets for ra-
tional therapeutics design.