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positive interpretation of LKB1 in stem cell programming and perpetuation (Udd and
Makela, 2011). Given that EMT activation, cell proliferation, apoptosis and other
cell features such as cell polarity, cell adhesion and motility involve pathways with
which LKB1 can and does cross talk, the apparent contradictions could arise from
the different signalling pathways with which LKB1 might be operating. One has to
differentiate stem cells into three types, namely embryonic stem cell, adult repro-
grammed stem cells and CSCs. Due to epigenetic relationships, CSCs might resem-
ble embryonic stem cells. CSCs share stem cell features with adult stem cells but
differ with regard to homoeostatic regulation, survival and perpetuation. These dif-
ferences would indeed flow from the different pathways operating in their generation
and are bound to impinge upon the function of modulators of stem cell biology, such
as LKB1 among others.
LKB1, Cytoskeletal Dynamics and Cell Motility and Invasion
Among the features that are most conducive cancer cell migration, invasion and
metastasis is the deregulation of cytoskeletal dynamics. Some tumour promoter
genes are known to destabilise microtubule dynamics, whilst suppressor genes pro-
mote microtubule stability. In fact it has been argued that destabilising cytoskeletal
dynamics might enhance cell invasion leading to metastatic spread. Contrary to con-
ventional wisdom, LKB1 phosphorylates and activates the AMPK-related MARK2
(microtubule affinity regulating kinase) and leads to Tau protein phosphorylation
resulting in the suppression of tubulin polymerisation (Kojima et al., 2007). This
has been confirmed in differentiating systems where LKB1 destabilises microtubule
dynamics (Mian et al., 2012).
Equally, epithelial structural integrity is based on adherens junctions involving
cadherins and catenin and desmosomes. Desmosomes are membrane plaques which
form links via connecting filaments and provide adhesion between cells and in turn
desmosomes are linked with intermediate filaments of the cell cytoskeletons of adja-
cent cells. It is of interest therefore that loss of LKB1 results in the deterioration of
desmosome-mediated intercellular adhesion and loss of structural integrity of epithe-
lia (Partanen et al., 2012). It might be recalled that the development of carcinomas is
characterised by a lack of desmosomes. Partanen et al. (2012) have gone on to show
that loss of LKB1
per se
may not lead to tumorigenesis but tumours do develop in
the presence of oncogenes. Generally consistent with this the introduction of LKB1
into LKB1-deficient HeLa cells has resulted in the activation of Rho GTPase and
promotion of actin filament assembly with focal adhesion (Xu et al., 2010).
Therapeutic Assessment of LKB1
The loss of LKB1 in many tumour types and the effects of it loss on invasion has
instilled investigations into potential benefits of reactivating its expression as a
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