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a b c d

e f g
Figure 1: Representative images of immunohistochemical positive reactions for CD31, D2-40, p-mTOR, RKIP, CD147, MCT1, MCT4 in non-muscle invasive
(c) and muscle invasive (a, b, d-g) urothelial bladder carcinoma (original magnifi cations indicated). (a) An embolus of malignant cells intravased in an
intratumoral blood vessel highlighted by CD31 (×400); (b) isolated malignant cells (*) and malignant embolus (†) invading intratumoral lymphatic vessels
highlighted by D2-40 (×200); (c) heterogeneous pattern of p-mTOR immunoexpression, with the intensity of staining of staining being lost from the luminal to
the basal cell layers of the urothelium (×100); (d) heterogeneous pattern of RKIP immunoexpression, with the tumor core being more intensely stained than the
invasive front (×100); (e) strong CD147 membrane immunoexpression in the inner layers of the tumor (×100); (f) immunoexpression of MCT1 in the malignant
urothelium (×200); (g) immunoexpression of MCT4 in the malignant urothelium (×200). MCT: Monocarboxylate transporter; p-mTOR: Phospho-mammalian target
of rapamycin; RKIP: Raf kinase inhibitor protein

suggest specifi c immunostaining of blood and lymphatic present. We did not fi nd signifi cant associations
[75]
vessels in histologically equivocal cases that require between clinicopathological parameters, vascular
confi rmation in order to better identify lymphovascular density, and p-mTOR expression. Nonetheless, p-mTOR
invasion that could have been missed during routine expression [Figure 1c] decreased with increasing stage
evaluation on HE-stained tumor sections, and to allow and was lost from non-tumor to tumor urothelium,
a more accurate discrimination between the 2 forms of particularly in muscle-invasive tumors, where
lymphovascular invasion. immunoexpression was only observed in cell clusters.
Angiogenesis was compromised in T3/T4-negative
As above, the occurrence of angiogenesis and cases; conversely, the group with T3/T4-positive tumors
lymphangiogenesis as potential targets for therapeutic had a quite poor outcome, as observed by others.
[73]
intervention in UBC is already under clinical These two patterns of expression, complete absence or
testing, with several compounds targeting the most presence in clusters of cells, are a possible consequence
relevant neovascularization signaling pathways. [41,64] of opposing biological settings mediated by mTOR
However, as with other types of cancer, the risk of signalling. There is the need to expand the research
refractoriness to VEGFs/VEGFRs signaling abrogation on larger and comprehensive series of UBC patients,
exists. [65] Compensatory mechanisms to VEGF with molecular effectors of upstream and downstream
blockade in UBC cell lines have been described. mTOR signaling, together with reproducible IHC and
[66]
While these anti-neovascularization compounds have molecular methodologies, and with in vivo and in vitro
clear value, additional efforts are being undertaken UBC models. This is in order to elucidate the role of
in the search of alternative pathways to abrogate the mTOR pathway in human UBC and to fi nd more
angiogenesis/lymphangiogenesis. The mammalian target appropriate target therapeutic strategies. Accordingly,
of the rapamycin (mTOR) intracellular pathway is recent studies characterizing UBC genetic background
an important signaling mediator in hypoxia-induced revealed chromosomal alterations not seen at the same
angiogenesis, besides transducing activator signals level in other types of cancers, namely, mutations of
[67]
for promoting cell growth. UBC pre-clinical genes involved in the PI3K/AKT/mTOR signaling
[69]
[68]
[72]
and clinical trials, [70,71] although few in number, pathway. [76]
have shown the anti-angiogenic effects of rapamycin
analogues. Nevertheless, levels of mTOR activation Tumor metastasis
in UBC tissue sections have been little explored, with The ability of malignant cells to leave a primary tumor and
controversial results being found. [73,74] We assessed to disseminate widely is commonly agreed to be the basis
phospho-mTOR (p-mTOR) levels in a series of 76 for metastasis formation, the mainly cause of death from
UBC tissue sections, where blood and lymphatic cancer. As above, angiogenesis and lymphangiogenesis
vessels were also specifi cally stained, in order to are integrate parts of the metastatic process, but additional
correlate angiogenesis and lymphangiogenesis with steps need to occur in order for a malignant cell or a
p-mTOR expression [Table 1]. Representative tumor cluster of cells colonize secondary sites. These interrelated
and non-tumor (normal-like or hyperplasic) areas were steps involve the expression of molecular promoters
60 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 2 ¦ July 15, 2015 ¦