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Review

Urothelial bladder cancer progression: lessons learned from the bench

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Julieta P. Afonso , Rui Freitas , Francisco Lobo , António Morais , Jorge Oliveira , Teresina Amaro ,
Rui M. Reis 1,2,5 , Fátima M. Baltazar , Adhemar Longatto-Filho 1,2,5,6 , Lúcio L. Santos 7,8
1,2
1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
2 ICVS/3B’s-PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
3 Department of Urology, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
4 Experimental Pathology and Therapeutics Research Center, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida,
4200-072 Porto, Portugal.
5 Molecular Oncology Research Center, Barretos Cancer Hospital, CEP 14784-400 Barretos, São Paulo, Brazil.
6 Laboratory of Medical Investigation (LIM 14), Faculty of Medicine, São Paulo State University, CEP 01246-000, São Paulo, Brazil.
7 Department of Surgical Oncology, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
8 Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia, 4200-150 Porto, Portugal.
Correspondence to: Dr. Julieta P. Afonso, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal. E-mail: julietaafonso@ecsaude.uminho.pt
ABSTRACT
Urothelial bladder carcinoma (UBC) is an intricate malignancy with a variable natural history and clinical behavior. Despite
developments in diagnosis/prognosis refi nement and treatment modalities, the recurrence rate is high, and progression from
non-muscle to muscle invasive UBC commonly leads to metastasis. Moreover, patients with muscle-invasive or extra-vesical
disease often fail the standard chemotherapy treatment, and overall survival rates are poor. Thus, UBC remains a challenge in
the oncology fi eld, representing an ideal candidate for research on biomarkers that could identify patients at increased risk of
recurrence, progression, and chemo-refractoriness. However, progress toward personalized medicine has been hampered by the
unique genetic complexity of UBC. Recent genome-wide expression and sequencing studies have brought new insights into its
molecular features, pathogenesis and clinical diversity, revealing a landscape where classical pathology is intersected by the novel
and heterogeneous molecular groups. Hence, it seems plausible to postulate that only an integrated signature of prognostic/predictive
biomarkers inherent in different cancer hallmarks will reach clinical validation. In this review, we have summarized ours and
others’ research into novel putative biomarkers of progression and chemoresistance that encompass several hallmarks of cancer:
tumor neovascularization, invasion and metastasis, and energy metabolism reprogramming of the tumor microenvironment.
Key words: CD147, lymphovascular invasion, mammalian target of rapamycin, monocarboxylate transporters, progression,
Raf kinase inhibitor protein, scoring system, urothelial bladder cancer

Introduction originate from transitional cells of the urothelium, while
approximately 5% and 2% are squamous and glandular
The urothelium, one of the slowest cycling epithelia in variants, respectively, while the remainder comprises
the human body, is constantly exposed to a variety of other rare subtypes. [3,4] The most well-established risk
[1]
potential carcinogens that can stagnate in urine for a few factors for bladder carcinogenesis are cigarette smoking
hours before urination. For that reason, the bladder is a and industrial exposures in the context of a number of
particularly high-risk organ for cancer development, and occupational settings. [5]
incidence and mortality from bladder cancer represent an
important public health problem. An estimated 429,000 Of all newly diagnosed cases of urothelial bladder
new cases of bladder cancer and 165,000 deaths occurred carcinoma (UBC), 70-80% arise as non-muscle
in 2012, worldwide. It was the 9th most common cancer invasive (NMI). These tumors, although without
for both sexes combined (4th in men, 15th in women). aggressive histopathological features, often experience
Sixty percent of cases occurred in more developed regions recurrence, and a subgroup of high-risk lesions
of the world (Europe, North America, North Africa). frequently progress to invasive forms. Conversely,
[2]
In these regions, more than 90% of all bladder tumors 20-30% originally present as muscle invasive (MI)
disease. Invasion of the muscular wall portends common
progression to metastasis. Despite radical cystectomy,
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radiation, and/or platinum-based chemotherapy, patients
Quick Response Code: often fail treatment, so the 5-year overall survival (OS)
Website:
www.jcmtjournal.com rate is < 50%, mostly due to chemotherapy resistance
and patient fragility. [4,6-9] Repeated relapses, occurrence
of progression, and chemoresistance make UBC the
DOI: [10]
10.4103/2394-4722.157377 costliest cancer to treat from diagnosis to death. Thus,
personalization of treatment could improve patients’

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 2 ¦ July 15, 2015 ¦ 57