Recently, the prospective isolation and characterization of cancer stem cells (CSCs) from various human malignancies revealed that they are resistant to radiation and chemotherapies. Therefore, CSCs may be the 'roots' and ideal target for therapeutic intervention. Here, we will focus on reviewing the historical perspective, recent literatures on bladder cancer stem cells and their clinical implications.
CSCs have been prospectively isolated from bladder cancer tissues from patient specimens, established cancer cell lines and xenografts, based on the expression of a combination of cell surface receptors, cytokeratin markers, drug transporters and the efficient efflux of the Hoechst 33,342 dye (side population). Further, global gene expression profiling of CSCs revealed an activated gene signature of CSCs similar to that of aggressive bladder cancer, supporting the concept that a tumor cell subpopulation is contributing to bladder cancer progression. Finally, our studies on the preclinical targeting of bladder CSCs in vitro and in xenografts using a blocking antibody for CD47 reveal promising efficacy.
Functionally distinct CSCs exist in human bladder cancer and can be prospectively isolated. Continuing research will be important to identify their cell of origin, programs balancing self-renewal and differentiation and to identify additional therapeutic options to target bladder CSCs.
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"Although both CIS and papillary lesions belong to superficial urothelial carcinomas, they show different morphologies as well as invasive potentials. Therefore, it has been suggested that CIS and papillary lesions arise from different cell types or harbor distinct mutations . Indeed, supportive evidence has shown that both CIS and invasive urothelial carcinoma arise from basal cells, whereas intermediate cells serve as the progenitors of papillary carcinomas . "
[Show abstract][Hide abstract]ABSTRACT: Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells in G1/S phases, which subsequently leads to apoptosis. And also metformin represses bladder cancer CSC repopulation evidenced by reducing cytokeratin 14 (CK14+) and octamer-binding transcription factor 3/4 (OCT3/4+) cells in both animal and cellular models. More importantly, we found that metformin exerts these anticancer effects by inhibiting COX2, subsequently PGE2 as well as the activation of STAT3. In conclusion, we are the first to systemically demonstrate in both animal and cell models that metformin inhibits bladder cancer progression by inhibiting stem cell repopulation through the COX2/PGE2/STAT3 axis.
"This receptor is strongly overexpressed in several cancer types including both hematological and solid tumors[80,91,109,110]. A high CD47 expression has been a poor prognostic factor for patients with these diseases[80,111,112]. CD47 is also highly expressed in tumor initiating cells (TICs) or cancer stem cells (CSC) where it is a marker of more aggressive tumor cells, with higher metastatic potential, and less sensitive to engulfment by macrophages, thereby escaping from immune surveillance while increasing cell proliferation through activation of the PI3K/Akt pathway[92,113114115116. Therefore, CD47 becomes an attractive target for therapeutic approaches with both antitumor and antiinflammatory properties and anti-CD47 antibodies are being tested with positive results in preclinical and clinical settings[80,111,112,117]. "
[Show abstract][Hide abstract]ABSTRACT: Inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Chronic inflammation plays a critical role in tumorigenesis. Tumor infiltrating inflammatory cells mediate processes associated with progression, immune suppression, promotion of neoangiogenesis and lymphangiogenesis, remodeling of extracellular matrix, invasion and metastasis, and, lastly, the inhibition of vaccine-induced antitumor T cell response. Accumulating evidence indicates a critical role of myeloid
cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge with the characterization of tumor-associated neutrophils (TANs). Recent studies show the importance of CD47 in the interaction with macrophages inhibiting phagocytosis and promoting the migration of neutrophils, increasing inflammation which can lead to recurrence and progression in lung cancer. Currently, therapies are targeted towards blocking CD47 and enhancing macrophage-mediated phagocytosis. However, antibody-based therapies may have adverse effects that limit its use.
Full-text · Article · Jan 2016 · Mediators of Inflammation
"Recent clinical studies have demonstrated that immune checkpoint inhibition, which restores anti-tumor T-cell immunity, is associated with a beneficial objective response and remarkably improves the prognosis of patients with advanced malignancies, including patients with BC . Chan et al. reported another potential type of immunotherapy against BC, where bladder CSCs express higher levels of CD47, a cell surface protein that provides an inhibitory signal for macrophage phagocytosis, compared with the rest of the tumor [20,139]. Blockade of CD47 with a monoclonal antibody resulted in macrophage engulfment of BC cells in vitro, suggesting that immunotherapy against CD47 could be effective in the treatment of MIBC. "
[Show abstract][Hide abstract]ABSTRACT: Bladder cancer (BC), the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs), which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.
Preview · Article · Dec 2015 · International Journal of Molecular Sciences