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Transfection of LKB1 into MDA-MB-435 breast cancer cells lacking the gene
inhibited invasion
in vitro
and
in vivo
led to inhibition of tumour growth and reduced
tumour associated microvessel density. Suppression of angiogenesis seemed to result
from suppression of angiogenic agents such as MMPs, VEGF and bFGF (Zhuang
et al., 2006). In contrast, LKB1 might activate TGF-β signalling, and in the absence
of LKB1 TGF-β signalling is suppressed. This implicates LKB1 as an important
element in TGF-β induced angiogenesis (Londesborough et al., 2008). There is an
implied suggestion here that the angiogenic effects of LKB1 can be uncoupled from
its ability to suppress cell proliferation. Londesborough et al. (2008) suggest that
changes in cell proliferation or apoptosis do not have a bearing on the effects of loss
of LKB1 on angiogenesis. It would not be out of place to state here that TGF-β can
signal by Smad-dependent as well as independent non-canonical pathways, which
might generate different outcomes in terms of cell proliferation, apoptosis and angio-
genesis (Sherbet, 2011a).
Signalling Systems in Cross Talk with LKB1
In common with several tumour promoter and suppressor genes discussed here,
LKB1 seems to collaborate with and its expression modulated by interacting path-
ways. LKB1 might also be regulated in its function by oncogenes or signalling sys-
tems by modulating those that are operational in tumour development, invasion and
spread. Looking directly at LKB1 as suppressor of cell proliferation, the Ras sig-
nalling system comes readily to mind. Activated Ras transduces its signals via three
distinct routs, namely the ERK1/2 pathway, the PI3K pathway and the Ral/GDS sys-
tem. The PI3K/Akt pathway signals can be carried along several sub-routes. Akt tar-
gets many genes, among them are the apoptosis inducing BAD gene, caspase 9 and
FasL as well as NF-κB (
Figure 28.1
). Of interest also is the activation of mTOR sig-
nalling with its implications for EMT (see Figures 3.1 and P2.1).
Of particular interest is the demonstration by Liu et al. (2012e) that loss of
LKB1 expression and K-Ras activation resulted in the formation of melanomas.
Furthermore somatic deletion of p53 and K-Ras activation also increased tumori-
genesis. Also inactivation of LKB1 led to the expansion of subpopulation of tumour
cells such as CD24+ cells that could be representing CSCs and participating in meta-
static spread.
Little collaborative signalling is evident in adenocarcinoma of the lung. Not
only was the incidence of genetic changes low, even in those cases where muta-
tions did occur, simultaneous changes of LKB1 or with EGFR were noted only in
a small number of patients (Suzuki et al., 2012). Okuda et al. (2011) found no con-
comitant mutation of LKB1 with Ras or EGFR in 5 that carried LKB1 mutation of
174 cases examined. LKB1 is reported to be mutated simultaneously with K-Ras,
EGFR and p53 in non-PJS mucinous bronchioloalveolar carcinomas; with K-Ras
in two tumours, with EGFR in two and with p53 in one tumour (Osoegawa et al.,
2011). LKB1 haploinsufficiency in conjunction with K-Ras has been associated
with murine and human pancreatic ductal carcinoma. Depressed levels of LKB1
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