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quality of life, and reduce the burden on health care Tumor neovascularization
systems.
The leading cause of mortality from cancer is not the
Clinical staging and histopathological parameters primary tumor itself, but the occurrence of metastasis
remain the “gold standards” for UBC diagnosis and from the primary tumor. [22,23] Disease dissemination
prognostic prediction. [11,12] However, they are not can occur by direct invasion of tissues and cavities
suffi cient to characterize individual biological features surrounding the primary site. However, the preferential
and clinical tumor behavior. Understanding disease course for metastases is spread through blood or
pathobiology could potentially add essential information lymphatic vasculature. Moreover, several preclinical and
to these classical criteria and contribute to more clinical studies have highlighted the preponderance of
accurately predicting prognosis and refi ne treatment. the lymphatic vascular system over the blood vascular
Ideally, the clinical use of standardized prognostic system with the involvement of the sentinel lymph node
and predictive biomarkers could allow the prediction being a standard diagnostic and prognostic parameter. [24,25]
of tumor recurrence through a non-invasive method, The occurrence of “de novo” vascularization is a
avoiding use of invasive techniques, such as cystoscopy crucial step in the metastatic route. In fact, the tumor
and biopsy, which cause signifi cant patient discomfort neovasculature not only supports the metabolic needs
[13]
and add substantial costs. Furthermore, it could allow of the malignant cells, but also establishes the routes
timely prediction of UBC progression, from NMI to for dissemination. The malignant cells overexpress
MI disease, particularly for high grade or carcinoma various angiogenic and lymphangiogenic growth
in situ lesions, guiding more vigilant surveillance and factors that alter the normal neovascularization
[14]
refi ning treatment strategies. Finally, it could allow the pattern, signifi cantly increasing blood and lymphatic
prediction of response to conventional cytotoxic therapies vessel density ( BVD and LVD, respectively). The
[26]
typically associated with chemorefractory relapse and link between neovascularization and lymphovascular
patient fragility. [15]
invasion signifi cantly worsens prognosis, with numerous
A cancer-related biomarker may be defi ned as a molecule reports on its association with risk of tumor recurrence,
produced by the tumor or by the organism in response progression, lymph node metastasis, and distant
to the tumor, measurable in sample matrices such as metastasis. [27,28] Accordingly, several preclinical models
tissue, blood, or urine, representative of the cancerous have demonstrated a signifi cant reduction in tumor
[16]
process, and reproducible, specifi c, and sensitive. growth and tumor associated-neovasculature when the
A reasonable number of UBC biomarkers, namely those expression of angiogenic and lymphangiogenic factors
involved in the key molecular pathways of urothelial was blocked. [29-31] Anti-angiogenic/lymphangiogenic
malignization (fi broblast growth factor receptor 3 and agents and targeted inhibitors, in monotherapy or in
tumor protein p53 mutations), seem to be prognostically combination with standard chemotherapeutic drugs, have
relevant. [17-19] Despite this, there is a substantial delay already reached the phase of clinical trials, and several
in translation into the clinic, and clinical trials with compounds have obtained approval from the Food and
molecularly targeted agents have been few in number Drug Administration agency. [32,33] While these agents have
and largely unsuccessful. There is the need to expand shown promising therapeutic effects, substantial evidence
[20]
biomarker research beyond the current focus on therapies of primary and acquired resistance has been reported.
[34]
directed at deregulated oncogenic or tumor suppressor Vessel normalization, by restoring physiological perfusion
pathways, and into new molecular portraits encompassing and oxygenation of tumor vasculature, has recently
all the hallmarks of cancer. In fact, recent medium- to emerged as a promising strategy to overcome resistance
[21]
high-throughput gene expression profi ling technologies to certain antiangiogenic therapies. [35]
and sequencing studies have revealed a multifactorial In the setting of UBC, angiogenesis has been extensively
scenario where additional molecular alterations seem reported, with several studies, including large-scale
to be involved in urothelial carcinogenesis and tumor approaches, indicating the independent prognostic value
progression. [8]
of high vascular endothelial growth factor (VEGF)
Biomarkers of UBC Progression: Lessons levels and BVD counts. [36-40] A number of clinical
Learned from the Bench trials with anti-angiogenic agents are ongoing for
UBC patients with NMI and MI disease. Reports on
[41]
In the next sections, we will summarize the contributions lymphangiogenesis, although fewer in number, also
of our group and of other authors to the research of point to a signifi cant role of lymphatic vessel formation
three poorly explored biological events that overlap in UBC spread. Overexpression of VEGF-C, VEGF-D,
several cancer hallmarks and seem to infl uence UBC and VEGFR-3, the key players of lymphangiogenesis,
progression: occurrence of tumor neovascularization, has been demonstrated in several studies, associating
loss of metastasis suppressor proteins, and metabolic with high LVD counts and lymph node metastasis, also
reprogramming of the tumor microenvironment. predicting poor prognosis. [40,42-45] In vitro and in vivo

58 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 2 ¦ July 15, 2015 ¦