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methylation (Djos et al., 2012). The inhibition of expression, for example of RASSF1,
which was hypermethylated in melanoma cell lines and tumour, was less conspicuous
in melanomas as compared with benign nevi. However, there might have been signifi-
cant contribution from mutation of B-Raf and N-Ras in tumour growth (Reifenberger
et al., 2004). In breast cancer also, methylation of RASSF1 has been noticed in a
majority of cases but markedly varied in degree, but none in control tissues (Sebova
et al., 2012). These authors also suggest that the degree of methylation might be
related to tumour size, lymph node involvement and TNM stage. Promoter methyla-
tion of RASSF1A was markedly greater in cervical tumours from patients with nodal
metastases than in patients who showed no metastatic spread (Malyukova et al., 2004).
Reduced RASSF1 expression correlated with tumour grade and nodal involvement in
oesophageal squamous cell carcinoma and nasopharyngeal carcinoma (Lo et al., 2007).
Similar inverse correlation with nodal metastasis has also been found in melanoma (Yi
et al., 2011). In gastric tumours, reduced cytoplasmic expression RASSF6 significantly
associated with invasion, regional lymph node metastasis as well as distant metasta-
sis and was reflected in poor disease prognosis. Expression of RASSF6 was lower in
metastatic lesions than in corresponding primary tumour (Wen et al., 2011). Also con-
sistent with other reports, methylation was encountered more often in metastatic than
in primary tumours. Methylation status in small bowel tumours and matched meta-
static lesions were examined for methylation of RASSF1. RASSF1 methylation was
encountered more frequently in metastatic tumours than in primary tumours (Zhang
et al., 2006b). This is obviously an interesting finding if it were properly established.
For, although matched primary and secondary tumours were studied, it is unclear how
many metastatic lesions showed increased methylation as compared with the corre-
sponding primary tumours.
A link between epigenetic silencing of RASSF1 and invasion and progression
has also been established for endometrial tumours (Liao et al., 2008). In some pae-
diatric tumours, the relationship between methylation of RASSF1 and the disease
process was not quite persuasive (Wong et al., 2004). However, Teng et al. (2011)
used mesenchymal stem cells derived from bone marrow to show that experimentally
methylating RASSF1 and the growth regulatory and tumour suppressor gene HIC
(hypermethylated in cancer) 1 transformed them into cancer stem cells. Furthermore,
upon implantation into immune compromised murine hosts the stem cells carry-
ing methylated RASSF1 developed into tumours, which upon serial transplantation
showed cells with CSC markers. This suggests the expansion of clones carrying the
marker into CSC subpopulations. One has to subject these findings to the caveat that
the CSC markers may not only display different patterns of presentation but also this
diversity or heterogeneity of marker expression might often depend upon the tumour
microenvironment. This is an important caveat in this series of experiments since the
CSC markers were identified after several serial transplantations. Notwithstanding
these reservations, it should be acknowledged that this is indeed a valuable exercise,
for cancer stem cells would be akin to adult stem cells and would represent a clone
that is amenable to the induction of differentiation, capable of self-renewal and pos-
sess proliferative potential. Therefore, they are potential targets for therapeutic inter-
vention routed through RASSF function.
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