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fact that ERα promotes cell motility and invasion. A further useful exercise would
have been to see how NDRG1 might have behaved in the backdrop of ERβ.
Metastasis Suppression by NDRG1
The metastasis suppressor function credited to NDRG1 flows from many accounts
of its ability to suppress invasion besides reports of its suppression in many forms of
cancer, EMT and angiogenesis. Cell lines overexpressing the gene showed downregu-
lated expression not only of MMP-9 but also of VEGF and IL-8, two major angio-
genic factors. In biopsies of pancreatic ductal adenocarcinoma, there is a significant
inverse relationship between NDRG1 expression and microvascular density and
depth of tumour invasion. Reduced NDRG1 was also associated with poor prognosis
(Maruyama et al., 2006). Fan et al. (2012) also found a similar inverse relationship
between microvascular density and NDRG1, but surprisingly NDRG1 expression
was higher in advanced stage of the disease than the earlier T1 stage. In a major-
ity of the tumours examined, NDRG1 was found in the cytoplasm, nuclear in 20%
and approximately a tenth of the specimens showed membrane located NDRG1. This
would have provided useful clues if only one knew what the distribution was like
in normal tissues. Enhanced expression has been reported by others (Hakan, 2004;
Chang et al., 2005) as Fan et al. (2012) have pointed out, but this might be related
to hypoxic conditions. With reduced vascularisation, the development of a hypoxic
environment is a possibility, but Fan et al. (2012) did not assess the state of hypoxia.
In an illuminating publication, Sibold et al. (2007) found NDRG1 expression in both
the cytoplasm and the cell membrane in HCC xenografts and further that NDRG1
expression increased in HIF-1α-dependent fashion. External stimuli alter the cellular
distribution of NDRG1 from the cytoplasm to the membrane. But whereas hypoxia
increased cytoplasmic levels, no relocation occurred in response to hypoxic signal.
However, relocation to the plasma membrane may indeed have implications for sig-
nalling, cell adhesion and motility and tumorigenesis.
As noted earlier, Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR kinases,
increased disease-free survival time of patients with NSCLC. The complexity in eval-
uating situations of this type arise from the fact that NO is an inducer of angiogenesis
and also incidentally of NDRG1. The latter is also induced by hypoxia, as discussed
earlier. So interpretations of increased expression of the suppressor would be subject
to certain caveats.
Views contrary to the suppressor function have been aired. Wang et al. (2004b)
claimed that NDRG1 is correlated with metastatic spread in colorectal cancer. They
found greater expression in primary tumours with metastases than those without
metastases. So they have suggested that NDRG1 might indeed promote metastatic
spread. However they found no difference in expression between primary tumour
and its metastases. Given that tumours are heterogeneous, if cells with higher
NDRG1 expression were more prone to metastasise one would have expected the
metastases to show higher NDRG1 expression of the corresponding primaries.
Nonetheless quite clearly one has to accept such a possibility. However, it ought to
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