Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 181

IDs and Tumour Angiogenesis
Aside from the overexpression reported in some tumours, more evidence
has emerged how it can support tumour growth and even metastatic spread.
Overexpression of some IDs promotes metastatic spread. ID1, ID2 and ID3 were
shown some time ago to be able to induce angiogenesis. Indeed many of the cases
where ID expression levels correlated with clinical stage and secondary dissemina-
tion also displayed greater degree of angiogenesis. Breast tumour cells either failed
to grow or grow into poorly vascularised and necrotic tumours when injected into
animals with altered genetic background of ID1+/− or ID3−/− (Lyden et al., 1999;
Benezra, 2001). In NSCLC, ID1 expression has been found to occur in parallel with
src kinase and MMP-9 (Rothschild et al., 2011). This is of interest since MMPs are
associated with tumour invasion and induction of angiogenesis. In endometrial can-
cers, ID1 expression was associated with increased microvessel density (Maw et al.,
2010). Ling et al. (2005) transfected the ID1 gene into prostate cancer cells and
showed the enforced expression of the gene-induced transcription of the VEGF gene
and secretion of VEGF. Prostate cancer cell xenografts also showed enhanced VEGF
expression in parallel with increased ID1 expression. In vitro assays indicated that
HUVEC cells differentiated into tubule formation when grown in media conditioned
with ID1 transfected cells. However, it is surprising that when xenografts were at
hand, no attempt was made to investigate or measure microvascular density.
A parallel upregulation of EGFR and VEGF with ID1 has been reported in colo-
rectal cancers, where these features also correlated with tumour stage (Meteoglu
et al., 2009), but a causal relationship between these is not visible. However, it is
worth reiterating here that EGF and HB-EGF do indeed possess angiogenic prop-
erties (Sherbet, 2011a). Whilst clinical stage does reflect progression, one ought to
recognise that colorectal cancer progression is characterised by the acquisition of
definable molecular features and these could have provided deeper insight into the
parallel upregulation of ID1, EGFR and VEGF.
In contrast with the tumour suppressor function discussed earlier, glioblas-
toma tissues have been found to overexpress ID4 and cell lines derived from these
tumours expressed ID4 10-fold higher than normal astrocytes. Highly vascularised
tumours formed when the high ID4 cells were xenografted. These tumours displayed
enhanced growth, but in vitro the high expresser cell lines did not show enhanced
proliferation or alteration in apoptosis. So the enhanced growth of the xenografts
seems to be a natural increase aided by higher vascularisation (Kuzontkoski et al.,
2010). Unfortunately angiogenesis was determined by histological assessment
and no markers of angiogenesis were employed and no attempt was made to elu-
cidate potential molecular mechanisms involved in the induction of angiogenesis.
Furthermore despite so much investment in terms of animal model, it is rather sur-
prising that the enhancement in angiogenesis was not followed up with the meta-
static spread of the xenografts.
A new link of much potential has been forged between angiogenic effect of ID4
and p53 mutation. ID4 is demonstrably overexpressed in the presence of mutant p53.
A gain of function mutant p53 together with the transcription factors p65 and E2F1