Is MKK a Metastasis Suppressor? - Therapeutic Strategies in Cancer Biology and Pathology - page 120

(Depeille et al., 2007). Ding et al. (2008) found that LeTx treatment reduced the
levels of phosphorylated ERK and p38 MAPK in vitro and prolonged treatment was
anti-proliferative. LeTx also substantially inhibited the release of VEGF, IL-8 and
bFGF. The in vivo effects were similar to those reported by Depeille et al. (2007).
Ample confirmation of these effects has emerged from the study by Huang et al.
(2008) that inhibition of MAPK kinase signalling inhibited the growth of renal cell
carcinoma xenografts and inhibited cell proliferation also of endothelial cells and
suppressed angiogenesis in vivo . Using a different model, namely the murine retinal
model, Bromberg-White et al. (2009) have shown that LeTx treatment induces sig-
nificant increase in the levels of secreted VEGF, but not interleukins or bFGF.
VEGF expression and release are enhanced by HIF in WM35 melanoma cell
lines suggesting the possibility that HIF, a pro-angiogenic agent, could be promot-
ing angiogenesis by this means. In cells carrying Ras or p53 mutations, HIF-induced
VEGF release increases (Shellman et al., 2003). This latter finding further adds
weight to the involvement of MKKs in the promotion of angiogenesis. FGF-2 stimu-
lates VEGF release via p44/p42 MAPK (ERK1 and ERK2)/SAPK/JNK pathway, but
activated p38 MAPK inhibits VEGF release (Tokuda et al., 2000). However, it ought
to be borne in mind that inhibition of one can transactivate the other (Sharma et al.,
2003).
Quite obvious is that different sub-routes of MAPK pathways might be engaged
by different ligands and oncogenes. According to Shin et al. (2005), H-Ras acti-
vates the Rac-MAPK kinase (MKK)3/6-p38 pathway and promotes invasion and
cell migration, which is probably attributable to the induction of MMP-2. But both
H-Ras and N-Ras activate the Raf-MEK-ERK and PI3/Akt pathways to prolifera-
tion and differentiation. Now with the reasonably well-established role in promot-
ing angiogenesis targeted inhibition of MKKs is worthy of clinical exploration. Of
some clinical significance is the report that emerged some time ago that LeTx sup-
presses PR and ERα (Webster et al., 2004). It is rather intriguing why findings of this
nature have not been confirmed and investigated further, especially in the light of the
importance in TNBC. It would be interesting to assess the effects of LeTx on TNBC
cell lines. One ought to recognise here that TEM8 has been implicated in endothelial
cell migration and tubule formation and CMG2 in endothelial proliferation.