Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 180

ID1, ID2 and ID3 Expression in Tumours
As opposed to ID4, IDs1-3 appear to be associated with more aggressive tumour and
also linked with invasion and angiogenesis as discussed below. ID1 expression has
often been noted to relate with aggressive tumours. At the experimental level, trans-
fection of ID1 into oesophageal carcinoma cells increased cell proliferation by the
activation of PI3K/Akt pathway, reduced apoptosis and enhanced metastatic spread
as assayed by experimental metastasis assay (Li et al., 2009a). But this cannot be
directly linked with the increased angiogenesis also noted in this study.
Correlation with tumour size, grade and stage has been frequently noticed. ID1 and
ID3 expression corresponded with the degree of differentiation in gastric adenocarcino-
mas, with higher expression in poorly differentiated tumours than in well-differentiated
counterparts. Their expression was also related to clinical stage. However, expression
levels did not relate unequivocally to metastasis. ID1 levels correlated with lymph node
metastasis, but not with distant metastasis. But this is at odds with the finding that high
expression levels were associated with poor prognosis in gastric cancer. High ID1 and
ID3 expression was associated with aggressive disease (Yang et al., 2011c). ID1 expres-
sion was related to size and to lymph node-positive status of oral carcinomas where it is
also related to tumour recurrence (Dong et al., 2010). Nuclear ID1 expression has been
detected in squamous and non-squamous cell carcinoma of the lung and ID+ samples
also expressed src kinase and MMP-9. Src kinase and MMP expression correlated with
each other and with tumour grade (Rothschild et al., 2011). Src kinase is a major regula-
tor of IDs. In many tumour cell lines, ID1 expression is downregulated when src kinase
is inhibited. Furthermore, src and ID inhibition decreased cell invasion (Gautschi et al.,
2008). Consistent with this is that ID1 expression has been allied with the depth of myo-
metrial invasion in endometrial cancers. So also in ovarian cancer, ID1 expression was
related to clinical stage. The survival rate was lower in patients with high ID1 expres-
sion than in those who had lower ID1 (Maw et al., 2009, 2010). ID1 and ID2 expres-
sions have been found to be overexpressed and ID3 and ID4 expressions were reduced
in prostate cancers compared to nodular hyperplasia (Yuen et al., 2006). But in some
cases, ID3 may be expressed highly with aggressive disease.
The significance of the patterns of expression, namely distribution of the IDs
between the cytoplasm and nucleus in relation to prognosis has been focused upon,
but no firm conclusions can be based on the currently available evidence, often based
on immunohistochemical assessment with the attendant pitfalls. For instance, there
are reports about the suppressor ID4 presence in the nucleus correlating with disease
parameters, but the accent appears on the cytoplasmic presence of ID1 and ID2, and
not infrequently ID3 with disease state. More investigations are warranted to ration-
alise the significance of the distribution pattern IDs. For instance, one needs to know
if the subcellular distribution pattern is a consequence of the importation of regu-
latory molecules into nucleus or a result of their export to the cytoplasm. In other
words, one has to look at the ratios of distribution than mere detection in the cellular
compartments before any rationalisation can be attempted and significance of pat-
terns of distribution interpreted in relation to the disease process.