Tumor microenvironment

Microenvironmental factors
Matrix metalloproteins (MMPs) degrade a range of
extracellular matrix and nonmatrix proteins. Since
MMP expression level has been implicated in can-
cer development, several polymorphisms in the pro-
moter regions of MMPs that might affect gene ex-
pression have been evaluated.
MMP1
MMP1 is a highly expressed interstitial collagenase,
which degrades fibrillar collagens. MMP1 is upregu-
lated by tobacco exposure [226] and overexpression
of MMP1 in tumors has been linked to tumor inva-
sion and metastasis [227,228]. A 1G/2G polymor-
phism in the MMP1 promoter was associated with
altered gene expression [229]. Promoters contain-
ing the 2G allele displayed higher transcriptional ac-
tivity than those with the 1G allele. An increased LC
risk was identified with the 2G/2G genotype by Zhu
et al. [230]. Two other studies, Su et al. [231] and
Fang et al. [232] both noted an increase in LC risk
with the 2G allele, but this did not reach statistical
significance.
MMP2
MMP2 is a gelatinase whose substrates include
gelatins, collagens, and fibronectin. The expression
levels of MMP2 have been commonly used to pre-
dict cancer prognosis. A promoter SNP (−1306C>T)
has been associated with reduced activity due to
a possible interference with the SP1-binding site
[233]. Interestingly, compared to the variant allele
associated with lower gene expression, the wild-
type allele exhibited an association with LC risk
with an OR of 2.18 (1.70–2.79) in a Chinese pop-
ulation [234]. Another promoter SNP (−735C>T),
which was linked with −1306C>T, was also associ-
ated with risk for the wild-type allele with an OR of
1.57 (1.27–1.95) [235] which retains the SP1 bind-
ing site as well as a higher transcriptional activa-
tion efficiency [236].Moreover, itwas noted that an
even higher risk was associated with the haplotype
containing the wild-type alleles at both loci and this
risk showed a multiplicative interaction effect with
smoking [235].
MMP3
MMP3 is a stromelysin whose substrates include
collagens, gelatin, aggrecan, fibronectin, laminin,
and casein. The most commonly studied MMP3
polymorphism is a promoter variant located at
−1171 nucleotide, containing either five or six
adenosines that may affect promoter transcription
activity [237]. In a Caucasian population, a hap-
lotype containing the 6A allele exhibited a higher
LC risk in never smokers [238]. However, in a Chi-
nese study, Fang et al. reported that smokers with
the MMP3 5A allele had a 1.68-fold (1.04–2.70) in-
creased risk to develop NSCLC [232].
MMP7
MMP7 is a matrilysin whose substrates include col-
lagens, aggrecan, decorin, fibronectin, elastin, and
casein.MMP7 is highly expressed in lungs of patients
with pulmonary fibrosis and other conditions asso-
ciated with airway and alveolar injury. The variant
allele of a promoter SNP, –181A>G, might lead to
higher promoter activity and increased mRNA lev-
els [239]. Consistently, the variant-harboring geno-
types, when compared to the common homozy-
gotes, have been proven to predispose to risk of
NSCLC [240].
MMP9
MMP9 is a gelatinase and the major structural com-
ponent of the basement membrane. Hu et al. re-
ported that two common nsSNPs, Arg279Gln and
Pro574Arg,might confer LC susceptibility in a dose-
dependent fashion [241].
MMP12
MMP12 is a metalloelastase required for
macrophage-mediated extracellular matrix pro-
teolysis and tissue invasion. A promoter SNP
(−82A>G) might regulate MMP12 expression
through modulating the binding affinity of tran-
scription activation protein 1 [242]. Another
nsSNP (1082A>G) leads to the substitution of
serine for asparagine. Although no significant LC
risk associations were identified for either SNP, a
haplotype containing the −82A and 1082G alleles
was associated with higher LC risk among never
smokers in comparison to haplotypes containing
−82G and 1082A [238].
Inflammation
Airway inflammation may promote tumorigenesis
through multiple mechanisms such as inducing ox-
idative stress and lipid peroxidation [243]. To date,
only a few polymorphisms in inflammation genes
have been evaluated for their roles in lung tumori-
genesis and the results have beenmostly discrepant.
Anti-inflammatory genes
The major functions of anti-inflammation genes
such as IL4, IL10, IL13, and PPARs are to resolve the
acute inflammatory reactions. Among these, IL10 is
produced by monocytes and lymphocytes and ex-
hibits multiple functions in the regulation of cell-
mediated immunity, inflammation, and angiogene-
sis [244]. Three SNPs in the promoter region of IL10
have been identified (−1082A>G, −819C>T, and
−592C>A). In a Chinese study, the variant allele
of the −1082A>G SNP was associated with a 5.26-
fold (2.65–10.4) increased LC risk [245], which was
in agreement with another study in small cell LC
[246]. The variant allele has been shown to affect
IL10 protein level through regulating gene tran-
scription [247–249].
Proinflammatory genes
Engels et al. [250] systematically evaluated a panel
of 59 single nucleotide polymorphisms (SNP) in 37
inflammation-related genes among non-Hispanic
Caucasian lung cancer cases (N = 1,553) and con-
trols (N = 1,730). They found that Interleukin 1
beta (IL1B) C3954T was associated with increased
risk of lung cancer and that one IL1A-IL1B hap-
lotype, containing only the IL1B 3954T allele, was
associated with elevated lung cancer risk. These as-
sociations were stronger in heavy smokers, partic-
ularly for IL 1B C3954T. IL1B activates a mixture
of inflammatory signaling mediators including NF
Kappa B, leading to an amplified proinflammatory
effect. A variable number of tandemrepeats (VNTR)
polymorphism in intron 2 of the IL1RN gene [251]
influences the expression of both IL1B and IL1RN
[252,253]. Lind et al. [251] observed an increased LC
risk in individuals with both the IL1RN∗
1 and the