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and suppressors of metastasis. Moreover, the success potential role of RKIP as a predictive biomarker has
of metastatic spread depends, not only on the intrinsic also been proposed, since its expression may mediate
properties of the tumor cells, but also on host feedback. [77] apoptosis induced by chemotherapeutic regimes. [86,87]

Genes inhibiting metastasis without blocking the ability Tumor metabolic reprogramming
of the transformed cells to develop a primary tumor Cancer is not only a complex genetic disease, but also a
are included in the group of metastasis suppressors. disease of deregulated bioenergetic metabolism. Elevated
Obviously, loss of expression of metastasis suppressor glycolytic rates are a common trait of malignancy.
[88]
genes is part of the metastatic genetic program, and a Warburg was the fi rst to describe the metabolic switch,
mandatory requisite for the success of the process. After known as “The Warburg Effect,” whereby a tumor cell
initial scepticism following the discovery of the Nm23 avidly consumes glucose and reprograms its metabolism,
gene, more than thirty protein coding/non-coding genes producing large amounts of lactate, even under
have been described that signifi cantly reduce the onset aerobic conditions. Lactate is the main source of
[89]
of metastasis without affecting the formation of the microenvironmental acidosis in tumors, contributing
primary tumor. Therefore, their loss occurs during cancer to an acid-resistant phenotype that supports increased
progression, not during transformation. [78,79]
migration and invasion abilities of cancer cells. [90-92] Its
In the UBC setting, progression of high-risk NMI dependence on monocarboxylate transporters (MCTs) for
tumors (high grade Ta/T1 tumors or carcinoma in situ) to transport across the plasma membrane directly implicates
muscle-invasive disease and ultimately, to extra-vesical MCTs in tumor behavior.
dissemination, carries a signifi cant risk of invasion and Monocarboxylate transporters belong to the SLC16
[4]
metastasis, despite radical surgical treatment. Inhibiting gene family, comprising 14 members, of which MCTs
biomarkers of progression and metastasis represents 1-4, the proton-linked MCTs, mediate infl ux/effl ux of
an attractive therapeutic approach, but restoring the monocarboxylates across the plasma membrane. MCT1
function of metastasis suppressor proteins, although and MCT4 are the best characterized MCTs in human
poorly explored, is also appealing. In this picture, the tissue, with MCT1 having ubiquitous distribution and
role of the metastasis suppressor Raf kinase inhibitor MCT4 being present in highly glycolytic tissues. The
[93]
protein ( RKIP) in cancer has been highlighted due to proper expression of MCTs at the plasma membrane
its ability to modulate several intracellular signaling depends on their interaction with CD147, a cell surface
[94]
pathways involved in cell differentiation, cell cycle glycoprotein implicated in extracellular matrix remodeling,
kinetics, apoptosis, epithelial to mesenchymal transition, angiogenesis, migration, and invasion and related to
and cell migration. [80,81] Given its pleiotropic abilities in chemoresistance-promoting events. CD147 and MCTs
[95]
maintaining cellular equilibrium, RKIP downregulation overexpressions have been described in several cancers,
is associated with metastatic events in an increasing associated with poor clinicopathological and survival
number of solid tumors. [82,83] Its preponderance in parameters. [95,96] Some in vitro models have demonstrated
[84]
UBC is largely unknown. In one study, low mRNA that CD147 downregulation sensitizes malignant cells to
levels were reported in NMI tumors when compared platinum-based therapy. [97-99] Therefore, metabolism-related
with normal urothelium. In our research, and for the cellular pathways involved in malignancy represent
fi rst time (to the best of our knowledge), we studied potential areas of therapeutic intervention.
81 tumor sections from UBC patients for RKIP
immunostaining [Table 1]. We observed tumors with Biological mechanisms that reprogram cellular energetics
[85]
a favorable clinicopathological profi le, namely, NMI in the setting of UBC are poorly characterized. Thus, we
tumors where LVI was absent, with a homogeneous investigated, in a series of tumor tissue sections from
expression of RKIP. Conversely, LVI occurrence was 114 UBC patients, a panel of three metabolism-involved
associated with a heterogeneous pattern of RKIP molecules [Table 1]. [100] The central protein seemed
expression, where expression intensity was lost from to be CD147. We had previously demonstrated the
tumor center to invasion front [Figure 1d]. Low RKIP prognostic impact of its overexpression in UBC when we
expression signifi cantly impacted prognosis, remaining an developed a model of UBC aggressiveness (n = 77) that
independent prognostic factor for disease-free survival. included classical clinicopathological (stage and grade)
As mentioned, similar associations concerning other and biological parameters (lymphovascular invasion
[54]
aggressive cancer types have been previously reported. and CD147 expression). [101] In fact, this scoring system
Clinically, a gradual decrease of RKIP expression was separated a low aggressive from the high aggressive
noted from benign to malignant tumors, and from those group, remaining as an independent prognostic factor for
to metastastic sites. [82,83] In the UBC setting, additional disease-free and OS. In the group of highly aggressive
studies are needed in order to confi rm our results and tumors, CD147 positivity was 87%, clearly adding
to expand research into therapeutic strategies that can prognostic information to the model [Table 1]. Thus, we
potentially restore RKIP functionality. Besides acting decided to re-evaluate this glycoprotein in a larger series,
as a biomarker of progression to metastatic disease, the exploring its crosstalk with MCTs and possible role in

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 2 ¦ July 15, 2015 ¦ 61