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Table of Contents
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 1-8

Molecular biology of urothelial carcinoma

1 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Medical Research, Chi Mei Medical Center; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
3 Institute of Biomedical Sciences, National Sun Yat-Sen University; Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
4 Department of Medical Research, Chi Mei Medical Center; National Institute of Cancer Research, National Health Research Institutes, Tainan; Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan

Date of Submission26-Nov-2020
Date of Decision04-Jan-2021
Date of Acceptance06-Jan-2021
Date of Web Publication1-Mar-2021

Correspondence Address:
Dr. Chien- Feng Li
Department of Medical Research, Chi Mei Medical Center, No. 901, Chunghwa Road, Yung Kang Dist., Tainan City 710
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_1_21

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Objective: Urothelial carcinoma (UC) is a common malignant tumor worldwide. Extensive genomic data analysis revealed that UC has a complex molecular character. From the perspective of cancer hallmarks reviewed the molecular biology participated in the tumorigenesis of UC. Data Sources: We inspected the results of multiple studies of UC focusing on the hallmarks of cancer. Results: UC has distinctive molecular pathways involved in sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, promotion of replicative immortality, induction of angiogenesis, activation of invasion and metastasis, genome instability and mutation, tumor-promoting inflammation, reprogramming of energy metabolism, and evasion of immune destruction. Conclusion: From the perspective of the hallmark of cancer, we revealed the many-sided biological behavior of UC.

Keywords: Hallmarks of cancer, molecular characterization, urothelial carcinoma

How to cite this article:
Liang PI, Chan TC, Shiue YL, Li CF. Molecular biology of urothelial carcinoma. J Cancer Res Pract 2021;8:1-8

How to cite this URL:
Liang PI, Chan TC, Shiue YL, Li CF. Molecular biology of urothelial carcinoma. J Cancer Res Pract [serial online] 2021 [cited 2022 Sep 28];8:1-8. Available from: https://www.ejcrp.org/text.asp?2021/8/1/1/310148

  Introduction Top

Urothelial carcinoma (UC) is the most common tumor type arising from the urinary tract.[1] The tumor can derive from the urothelium of the upper urinary tract (renal pelvis and ureter) or the urothelium of the lower urinary tract (urinary bladder and urethra). Previous studies have shown that the biological behavior and the gene expression profiles of UCs arising from both locations are highly similar.[2],[3] This finding indicates that tumorigenesis of UC from anywhere in the urinary tract employs common pathways. In developed countries, the incidence of upper urinary tract UCs (UTUCs) is less frequent than that of urinary bladder UCs (UTUBs), and the ratio of the incidence of UC in the renal pelvis, ureter, and urinary bladder is approximately 3:1:51. However, the prevalence of UTUCs is high in certain populations such as those with Balkan endemic nephropathy, Chinese herb nephropathy, or phenacetin abuse.[2],[4] In Taiwan, the ratio of the incidence of UC in the renal pelvis, ureter, and urinary bladder is approximately 1:2.08:6.72. The higher incidence of UTUC in Taiwan may partly be explained by the presence of environmental pollution and the increase in herbal consumption.[3] Currently, the carcinogenesis of UC is still poorly understood, despite the increasing number of studies identifying the prognostic value of biomarkers.

Histologically, UC was graded as low grade or high grade according to nuclear features, pleomorphism, mitosis, and cell arrangement. Low-grade UC (LGUC) is characterized by enlarged but monotonous nuclear features, loss of polarity, and rare mitosis [Figure 1]. These cases frequently show papillary configurations and rarely develop stromal invasion. In contrast, high-grade UC (HGUC) has moderate-to-marked nuclear pleomorphism, prominent nucleoli, and frequent mitosis. The papillary structure is frequently fused, and it tends to develop into an invasive tumor. Occasionally, carcinoma in situ (CIS) is associated with HGUC, which shows high-grade tumor cell pagetoid spreading along the surrounding urothelium.[5] In the urinary bladder, LGUC is frequently associated with activating point mutations in the gene that encodes fibroblast growth factor receptor 3 (FGFR3).[6] For UC of the urinary bladder (UBUC), tumors that invade the proper muscle layer have a worse outcome than those that do not and thus need more aggressive treatment. Currently, many classification systems have been published and are available for molecular subtyping of UBUC. Some of them focus mainly on either nonmuscle-invasive bladder cancer (NMIBC), such as the UROLMOL[7] system, or muscle-invasive bladder cancer (MIBC), such as the Cartes d'Identité des Tumeurs-Curie,[8] University of North Carolina,[9] MD Anderson Cancer Center,[10] and Cancer Genome Atlas (TCGA)[11] systems. Other systems, such as the LUND[12] and Baylor[13] systems, can be applied to both NMIBC and MIBC. Although the complexity and taxonomy are different between each system, there are similar clusters across the different systems. For example, in MIBC, a group of cancers rich in PPARG and estrogen receptor transcription can be identified across the systems. They share similar biomarkers with luminal subtypes of breast cancer and preserved uroplakins and KRT20.[10] FGFR3 mutations can be detected in more than half of this subgroup. Histologically, tumors carrying these two molecular changes usually show papillary configurations. In addition, patients with this subtype of MIBC, the luminal-papillary (LumP) type, have a relatively good outcome.[14],[15] The UROLMOL system classified NMIBC into three subclasses. Class 1 consists mostly of low-grade tumors with mutations in early cell cycle genes. Class 2 NMIBC shares similar luminal cluster genes with Class 1 tumors but has mutations in late cell cycle genes and regularly progresses to MIBC over time in high-grade tumors. Class 3 tumors show basal-like gene expression.[7] The well-characterized molecular features not only provide information on UBUC behavior but also offer crucial guidance for their treatment.
Figure 1: A brief review of bladder carcinogenesis. The process starts with loss of heterozygosity of related chromosomes in the normal bladder epithelium and gives rise to flat atypia or papillary hyperplasia. Around 80% of the lesion developed into low-grade papillary urothelial carcinoma after associated molecular aberrations occurred. A small portion (~15%) of these lesions developed into high-grade papillary urothelial carcinoma after disruption of the tumor suppressor genes. On the other hand, 20% of cases may acquire the loss of function of the p53 and developed urothelial dysplasia. The lesions may progress into urothelial carcinoma in situ which frequently associated with loss of expression of RB protein. High-grade papillary urothelial carcinoma and urothelial carcinoma in situ have a high propensity to develop into invasive urothelial carcinoma

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Similar to those in UBUC, FGFR3 and TP53/MDM2 gene mutations are frequent genetic events in UTUC. Low-grade tumors regularly have activating FGFR3 mutations and lack TP53 mutations. However, the TP53 mutation is more prevalent in high-grade UBUC. One-third of high-grade UBUCs have FGFR3 mutations instead of TP53 alterations and have a relatively promising clinical outcome.[16] UTUC also has a higher prevalence of HRAS mutations and a lower prevalence of RB1 and ERBB2 mutations.[17] Somatic microsatellite instability (MSI) has been reported in UTUC. A previous study showed that DNA mismatch repair (MMR) deficiency is observed in 7% of UTUC cases.[18] The transcriptome of UTUC is less characterized, in contrast to that of UBUC, probably due to the rarity of this tumor worldwide. The first comprehensive transcriptomic analysis of UTUC was conducted by Moss et al. and involved 31 untreated snap-frozen tumor samples. Four clusters of UTUC were identified: cluster 1 resembled the UBUC luminal subtype; cluster 2 resembled the UBUC basal subtype, had 100% FGFR3 mutations, and low bladder recurrence; cluster 3 had 100% FGFR3 and 71% PIK3CA mutations, no TP53 alterations, and high bladder recurrence; and cluster 4 had 50% TP53 mutations, frequent high-grade, advanced-stage disease, and shorter survival. UTUC of cluster 3 and cluster 4 showed a trend of poorer overall survival.

Loss of heterozygosity is considered an early genetic event of UC development and can be found in premalignant lesions of UC, which are also known as low-grade intraurothelial neoplasia.[19] From here, the tumors progressed along one of the two different tracks of UC development. Most of them developed noninvasive papillary LGUC, which has a characteristic exophytic papillary configuration. Approximately 10%–20% of these LGUCs will transform into more aggressive HGUCs, which tend to invade the underlying stroma. A small portion of low-grade intraurothelial neoplasia progresses to high-grade intraurothelial neoplasia/CIS, which also frequently develops into invasive UC.[20],[21] Recently, an analysis of high-throughput data revealed that UCs have complex genomic alterations and thus confer different biological behaviors.

The concept of hallmarks of cancer (HOCs) was introduced by Hanahan and Weinberg to provide a logical framework for understanding the remarkable diversity of neoplastic diseases.[22],[23] The number of HOCs has been expanded and refined during the past two decades. To better illustrate the many facets of UCs, we will discuss the molecular biology behind the development of UCs from the perspective of the ten HOC.

  Sustained Proliferative Signaling Top

Sustained proliferation of neoplastic cells is the fundamental feature of cancer. Increased mitogenic signaling is the key to maintaining the growth of cancer cells. Cancer can increase the signal through increased growth factor ligand production, elevating the growth receptor levels on cancer cells, altering the structure of the receptor, or modifying elements of the downstream cascade.[22],[23] The past two molecular changes, considered growth factor-independent pathways, are important for the development of UC. Activating point mutations of the gene that encodes FGFR3, a tyrosine kinase receptor, are consistently observed in LGUCs. The persistent activation of FGFR3 activates the downstream mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which are important for the regulation of cell growth and proliferation.[24] HRAS is a member of the GTPase family and is a downstream element of the FGFR3 receptor. Mutation of the HRAS oncogene is another important genetic alteration in UCs and has a similar effect on downstream pathways as FGFR3. Their mutations are mutually exclusive.[25] Another frequent genetic alteration associated with LGUCs is mutations in the PIK3CA gene, which consistently activate the PI3K/AKT/mTOR pathway.[26] Unlike HRAS alterations, PIK3CA is associated with concurrent FGFR3 mutations. LGUC harboring PIK3CA/STAG2 mutations has a higher propensity to develop into noninvasive HGUC.[27] This finding highlighted the critical role of the PI3K/AKT/mTOR pathway in the development of HGUC. These molecular alterations are considered important signals that promote urothelial hyperplasia to LGUC.[6]

  Evasion of Growth Suppressors Top

To benefit from the sustained growth signals, tumor cells must bypass the sturdy cell cycle to proliferate. This process is tightly regulated by the products of tumor suppressor genes.[22],[23] The TP53 and RB proteins play a central role in regulating the process. In HGUC, inactivation of TP53 and RB genes is key molecular features. Zhang et al. showed that transgenic mice harboring the SV40T transgene developed bladder tumors mimicking human urothelial CIS and invasive UCs.[21] TP53 regulates the cell cycle by activating the transcription of the CDKN1a gene to generate the p21 protein. In HGUCs, TP53 is commonly affected by missense or loss-of-function mutations. Such mutations can be easily displayed using immunohistochemistry, as HGUC normally shows diffusely positive or negative staining results. Upon phosphorylation, RB releases E2F and promotes the expression of genes needed for the cell cycle to progress. Concurrent defects of these suppressor genes are important in promoting, but not initiating, UC invasiveness.[28] The CDKN2A mutation is also a frequent genetic event in UCs. Through different types of splicing, CDKN2A encodes the p14 and p16 proteins. The p14 protein inhibits the transcription of the MDM2 gene, which in turn prevents the degradation of TP53.[29] A previous study revealed that homozygous deletion of CDKN2A is frequently associated with FGFR3-mutated UCs and contributes to tumor aggressiveness and invasiveness.[30] The phosphatase and tensin homolog gene is another tumor suppressor gene that is also found to promote UC invasiveness.[31] We can conclude that Ras pathways are primarily involved in papillary tumor formation pathways, and genes associated with tumor suppression are more likely to confer increased aggressiveness.

  Resistance to Cell Death Top

Apoptosis is one of the defense mechanisms to prevent the body from developing cancer.[32],[33],[34] The increased cancer-promoting signaling and DNA damage associated with hyperproliferation are stresses that trigger apoptosis. Tumor cells usually develop strategies to bypass apoptosis throughout the tumorigenic process.[22],[23] The loss of TP53 function hinders the response of apoptosis to stress.[35] Previous results showed that the Fas receptor is located on the cell surface and activates the extrinsic apoptotic pathway when binding with FasL. Invasive UCs tend to decrease Fas expression on the surface to avoid apoptosis and may release soluble Fas to neutralize FasL. UCs with these alterations usually behave more aggressively clinically.[36],[37] Other apoptosis-related markers, including caspase-3, BCL-2, and survivin, also have prognostic impacts on surviving patients.[38] Autophagy is a physiological process that enables cells to break down cellular organelles and recycle them for further biosynthesis and energy metabolism.[39],[40] This process is kept in a basal state for normal cells and can be activated upon exposure to stress. Cancer cells can utilize this process to survive through stresses induced during treatment.[41] Autophagic activity is upregulated in UCs. The activity is AMPK/mTOR dependent and is associated with tumor progression. Inhibiting autophagy upon cell starvation activates intrinsic apoptotic pathways.[42],[43],[44] The crosstalk between autophagy and apoptosis can be an important target for the treatment of UCs.

  Promotion of Replicative Immortality Top

Most normal cells go through a limited number of cell growth and division cycles that are tightly regulated by telomeres.[45],[46] Telomeres are composed of multiple tandem repeats of short GT-rich sequences and protect the end of chromosomes from loss of genetic materials and formation of unstable chromosome structures. The telomeres become shorter as DNA replicates and eventually lose their capping function. The shortened telomere activates DNA damage responses and triggers cell cycle arrest, and the cells enter an irreversible nonproliferative but viable senescence state. Telomerase, composed of telomerase reverse transcriptase (TERT) and a telomerase RNA component, is a specialized DNA polymerase that adds telomere repeat segments to the ends of telomeric DNA to counteract the progressive loss of telomeres. In normal nongermline tissue, telomerase activity is suppressed through the repression of TERT gene transcription.[23],[47] However, telomerase activity can be detected in almost all cancers, including UCs, reflecting the fundamental requirements for cancer cells to replicate repetitively. TERT promoter mutation is an early event in UC tumorigenesis and promotes the upregulation of telomerase activity in UCs.[48],[49] TERT promoter mutations can be detected in 60%–80% of UCs and do not occur in benign urothelial proliferation; thus, they can be useful diagnostic tools for the detection of UCs.[48],[50] In addition to telomere lengthening, telomerase and TERT participate in various biological processes, including cell survival, apoptosis, and DNA repair.[47]

  Induction of Angiogenesis Top

Vascular networks are crucial to maintain the delivery of nutrients and oxygen and remove waste products in tumors.[22],[23] During tumorigenesis, increased metabolic activity and energy consumption create a hypoxic state within the tumor and activate the “angiogenic switch.”[51] Hypoxia inducible factor 1 (HIF-1) production is increased, resulting in the activation of vascular endothelial growth factor receptor-1 (VEGF1) and VEGFR-1 transcription.[52] In UC, HIF-1a is overexpressed and is correlated with a high proliferation index, increased VEGF expression, increased microvessel density, and poor survival.[53],[54] VEGF-A plays a central role in angiogenesis. This molecule is overexpressed in UBCs and likely confers tumor aggressiveness.[55],[56] Interestingly, the mRNA levels of VEGF and angiopoietins are significantly higher in low-grade and low-stage UC than in their high-grade and high-stage counterparts. VEGF immunostaining also revealed a lack of “hot spot” expression in HGUCs. This evidence suggests that VEGF activity is high during the early tumorigenesis of UCs and decreases as vascular remodeling is less pronounced during the late stage.[57]

  Activation of Invasion and Metastasis Top

The invasion and metastasis of cancer involve multistep processes.[22],[23] Although many studies have disclosed regulatory molecules associated with tumor metastasis, the complex mechanism of invasion and metastasis is still unclear. Epithelial–mesenchymal transition is an important step in the beginning of this process. In UCs, loss of cell adhesion markers and an increase in mesenchymal markers are associated with invasive tumors and higher tumor grades.[58] E-cadherin is a cell–cell adhesion glycoprotein, and loss of function contributes to cancer progression, invasion, and metastasis. In UTUBs, loss of E-cadherin expression is associated with tumor recurrence and tumor progression.[59],[60] Integrins are transmembrane receptors involved in cell-extracellular matrix (ECM) adhesion. The crosstalk between E-cadherin and integrin plays a role in tumor invasion and metastasis.[61] When ITGA5, encoded by integrin alpha 5, was knocked down, UCs showed increased E-cadherin expression, a downregulated “stemness” phenotype, and impeded tumor metastasis.[62] The “stemness” phenotype refers to the expression of stem cell markers that are normally observed in embryonic and adult stem cells. Tumor cells with this phenotype usually show self-renewal and multilineage differentiation potential and are thus cancer stem cells. UCs with “stemness” phenotypes have a higher propensity to metastasize.[63] Several stemness-related pathways have been shown to be involved in the UC metastatic process including the Hedgehog, Notch, Wnt/beta-catenin, and PI3k/Akt pathways.[64] The interaction between tumor cells and their surrounding microenvironment also determines their metastatic propensity.[65] This microniche is orchestrated by inflammatory cells, stromal cells, ECMs, and soluble components. Although many problems have been addressed, many questions still need to be answered.

  Genome Instability and Mutation Top

The frequency of mutation in the genome is determined by the sensitivity to mutagenic agents and the integrity of the genomic maintenance machinery. Disruption of the maintenance machinery causes widespread genome instability in human cancer. This phenomenon is instrumental for tumor progression, as evolving tumor cells can accumulate favorable genotypes for tumor survival.[23] Deficiencies in MMR systems can cause MSI, resulting in the accumulation of mutations in the short tandem repeats of DNA and tending to cause DNA mismatch errors. Inactivation of the MMR gene (MLH1, PMS2, MSH2, or MSH6) is either caused by an inherited mutation (Lynch syndrome) or sporadic events. MMR deficiency/MSI-high events are found in <1% of UCs of the urinary bladder but can occur in up to 20% of UCs of the upper urinary tract.[66],[67] With advances in molecular techniques, the evaluation of tumor mutational status is currently possible. Tumors with a high tumor mutational burden (TMB) are associated with a good response to immune checkpoint inhibitor therapies.[68] This finding may be due to tumors with high TMB generating more neoantigens and thus readily being recognized by the immune system. UC has relatively high somatic mutation frequencies, along with lung cancer and melanoma.[69] The mutation frequency shows a pattern of TCW > T/C mutations (where “W” corresponds to either A or T, with C to T transitions or C to G transversions), which is consistent with the characteristic mutational signature caused by the “apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like” (APOBEC) family of cytidine deaminases.[70] The APOBEC family has 11 members and is involved in C > U deamination in single-stranded DNA. TCGA and BGI datasets showed that UCs enriched with the APOBEC mutational signature (APOBEC-high) had better overall survival than those with low or no enrichment (APOBC-low). In addition, APOBEC-low UCs tend to be seen in LGUC and are associated with Asian ethnicity. Of all members of the APOBEC family, only APOBEC3A and APOBEC3B expression is associated with UC total mutational burden. APOBEC-high UCs tend to have mutations in DNA repair genes and chromatin regulatory genes such as TP53, NCOR1, KMT2C, KMT2A, ATR, BRCA2, and ARID1A. However, APOBEC-low UCs have a more frequent mutations in FGFR3 and HRAS.[71] It is likely that increased replicative stress and disruption of DNA repair genes can promote APOBEC mutagenesis.[72],[73],[74]

  Tumor-Promoting Inflammation Top

The infiltration of inflammatory cells in cancer is considered a sign of the immune response to eradicate the tumor.[75] Later, it was found that this tumor-associated inflammation can exert a protumoral effect on cancer. Similar to wound healing, inflammatory cells release growth signals, proangiogenic factors, and ECM-modifying enzymes into the tumor microenvironment, facilitating tumor growth.[76],[77],[78],[79] Tumor-associated macrophages (TAMs) have been widely studied in numerous cancers. Increased TAMs have been associated with poor outcome in some cancer types (breast, head and neck, melanoma, etc.) but not the others (colorectal and stomach).[80] There are two different phenotypes of macrophages: the antitumoral activated phenotype (M1) and the protumoral immunosuppressive phenotype (M2).[81] Increased M2-like CD163+ TAMs in UCs are associated with tumor recurrence and failure of Bacillus Calmette–Guerin therapy.[82],[83] In vitro studies showed that bladder tumor cells were able to secrete M2 polarizing cytokines and transformed macrophages.[84] Notably, interleukin (IL)-10 can induce immunosuppressive macrophages and suppress activated T-cells. In addition, IL-10 induced the expression of programmed death ligand 1 (PD-L1) on macrophages.[85]

Based on solid evidence of a tumor-promoting role for TAMs, it is worth identifying treatment strategies for TAMs.[80] Multiple studies have evaluated the value of the neutrophil-lymphocyte ratio (NLR) in predicting survival or treatment outcome in UC. A systematic review revealed that a high NLR is correlated with worse overall recurrence-free and cancer-specific survival.[86] High tumor-associated neutrophils (TANs) can be seen in UCs and are associated with advanced tumor stage. Higher levels of IL-8 and transforming growth factor (TGF)-beta are released by UCs than by normal urothelium.[87],[88] IL-8 is a potent chemoattractant for neutrophils, and its circulating level correlates with the NLR in UCs.[88],[89] TGF-beta is responsible for transforming neutrophils into N2 phenotypes. N2 neutrophils release high levels of arginase and matrix metalloproteinase-9, which is known to confer tumor aggressiveness.[90] Based on solid evidence that the innate immune system influences downstream adaptive immunity, building a therapeutic strategy to manipulate intratumoral innate immunity is important.

  Reprogramming of Energy Metabolism Top

To overcome deregulated cell proliferation, tumor cells will reprogram their energy metabolism for more efficient use of fuel and oxygen. Otto Heinrich Warburg demonstrated in 1924 that cancer cells are prone to glycolysis in glucose metabolism even with the support of adequate oxygen.[91],[92],[93] To overcome the less efficient ATP production, tumor cells upregulated glucose transport GLUT1 expression to facilitate the transport of glucose into the tumor cells. In urothelial neoplasms, GLUT-1 is mostly expressed in UCs but not in benign neoplasms. In addition, the upregulation of GLUT1 positively correlated with tumor grading and staging.[94],[95] The upregulation of glycolysis in UCs likely participates in the early phase of tumorigenesis. As the tumor progresses, pyruvate metabolism increases and eventually becomes the main source of energy for the tumor.[96] Lactate dehydrogenase isoform A plays a major role in maintaining glycolysis in tumor cells and converts glucose storage into lactate. The increase in lactate production in UC results in indirect modification of the tumor microenvironment and leads to tumor progression.[97] In addition to aerobic glycolysis, other metabolic pathways were also likely reprogrammed in UCs including the lipid metabolic pathway. Previous studies showed that fatty acid oxidation and fatty acid synthesis were upregulated in UCs.[97] Fatty acid synthase (FASN) is a single multienzyme complex that catalyzes fatty acid synthesis. Previous studies have shown that FASN overexpression participates in UC tumorigenesis and triggers apoptosis when exposed to a FASN inhibitor; thus, FASN is a novel therapeutic target.[98],[99] In addition, various metabolites have been identified in the urine or serum of patients and show correlations with tumor involvement and/or grading.[97],[100],[101] These molecules can be useful biomarkers to identify a patient with UCs or for the detection of tumor recurrence.

  Evasion of Immune Destruction Top

Our long-standing belief is that the human body is under constant immune surveillance and that incipient cancer cells are readily removed from the system.[23] Dendritic cells (DCs) mainly present antigens to T-cells and activate them. In UCs, there is an increased number of immature DCs expressing low HLA-DR, CD80, and CD86.[102] Immature DCs fail to activate T-cells and may shift T-cells toward a regulatory (Treg) phenotype.[103] Patients with UCs also have higher levels of Th2 cytokines (IL4, Il5, and IL10) and lower levels of Th1 cytokines (IL2 and IFN-gamma) in their serum.[104] This evidence indicates that UCs evade immune destruction by shifting away from the cell-mediated response. CD8+ T-cells are important for immune-mediated tumor destruction and have been at the center of immune-oncology during the past decade. A previous study observed a favorable outcome in a subset of UCs with increased intratumoral CD8+ T-cells; these cells can be used as a predictive marker for treatment response when coupled with FoxP3+ Treg cells. Exhaustion and functional impairment of T-cells can be seen in many cancers. The dysfunctional CD8+ T-cells expressed high levels of inhibitory receptors including PD-1, TIM-3, and Lag-3. The overexpression of PD-L1 on TAMs and tumor cells induced CD8+ T-cell exhaustion when binding to PD-1, thus impairing the CD8+ T-cell antitumor response. The PD-1/PD-L1 axis is the major target of many checkpoint inhibitor anticancer drugs. Nevertheless, activated and functional CD8+ T-cells can also express high levels of PD-1, which may hamper the treatment effect of anti-PD-1.[105]


Most of the experiments mentioned above were conducted using UBUCs. The debate of whether UBUCs and UTUCs share similar biological behavior and molecular alterations is beyond the scope of this paper. However, we would like to note that the frequency of the involved molecules or pathways can be different in these two tumors. For example, RB1 gene mutations are common in UBUCs (12.9%) but are not detected in UTUCs.[106] MSI-high is seen in <1% of UBUCs but is detected in up to 20% of UTUCs.[49] Thus, although UBUC and UTUC share many similarities, careful consideration should be given when applied to UTUC. More studies are warranted to understand the biology of UTUC.

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