Suppressor Function of NDRG1 - Therapeutic Strategies in Cancer Biology and Pathology - page 101

be mentioned here that a diametrically opposite view has been expressed in respect of
colorectal cancer itself. Strzelczyk et al. (2009) indeed found that patients with reduced
expression of NDRG1 showed shorter 5-year survival than those with unchanged or
increased NDRG1 expression. In fact reduced NDRG1 expression was markedly more
frequent in and associated with TNM (tumour/node/metastasis) stage of progression.
In support of those who advocate metastasis promoter function, one can cite
reports of apparent induction of angiogenesis. In NSCLC cells suppression of
NDRG1 expression using siRNA resulted in growth inhibition of xenografts in vivo ,
but induced the expression of VEGF and IL-8. In resected tumours, microvessel
density correlated with nuclear NDRG1 (Azuma et al., 2012). Nishio et al. (2008)
studied cervical adenocarcinomas for possible relationship between NDRG1 and
clinical features of aggressive behaviour of the carcinomas. They found a close cor-
relation between NDRG1 expression and lymphovascular invasion and lymph node
metastasis and it was associated with poor prognosis. NDRG1 also correlated with
angiogenesis leading them to suggest induction of angiogenesis was the reason for
the apparent link between NDRG1 expression and poor prognosis. A similar situa-
tion seems to exist in hepatocellular carcinoma. NDRG1 was overexpressed in the
carcinomas as compared with normal liver tissue, and it was accompanied by vascu-
lar invasion. The expression status correlated with tumour stage and grade and with
shorter overall survival (Chua et al., 2007). Recently Nagai et al. (2011) investigated
a large series of breast cancer patients for NDRG1 and 10-year follow-up for prog-
nosis. Around half of nearly 600 patients expressed NDRG1 and this directly corre-
lated with shorter disease-free and overall survival. Toffoli et al. (2009) examined the
effects of intermittent hypoxia which causes endothelial dysfunction and reported to
increase endothelial cell migration. Intermittent hypoxia increased NDRG1 protein
expression and suppression of NDGR1 by NDGR1-siRNA transfection decreased
endothelial cell migration estimated by the qualitative scratch assay in EAhy926
endothelial cell cultures.
The problems associated with and inherent in interpreting NDRG1 expression
and tumour progression derive from the intervention of hypoxic stress and HIFs
which confer marked growth advantage, as well as the tumour-associated angiogen-
esis which is vital for tumour spread. Adaptation to the hypoxic environment via
the HIFs confers upon tumour cells, the faculties of cell proliferation and survival,
renewal and maintenance of CSCs, and invasion. The phenotypic outcome would
depend upon the target genes and these might inhibit or promote progression. To
complete the picture, genetic or environmental stimuli besides hypoxia can induce
HIFs, which in turn would influence tumour growth and progression. The evidence is
overwhelmingly in favour of tumour promotion, so much so that HIFs are regarded
as legitimate targets for therapeutic intervention.
Some clinical studies are under way to study the effects of HIF suppression. Of note
are studies of antisense HIF-1α oligonucleotide (NCT01120288), cardiac glycoside
digoxin in breast cancer (NCT01763931), and rapamycin derivative RAD001 in colo-
rectal carcinoma (NCT01047293), PX-478 ( S -2-amino-3-[4−- N , N ,-bis(2-chloroethyl)
amino]phenyl propionic acid N -oxide dihydrochloride) was reported to inhibit the
growth of xenografts HT-29 colon cancer cells by inhibiting HIF-1α and VEGF