4.3 Identified molecular pathways in bladder cancer
Modification of different molecular pathways and changes in living
organisms such as mutations, alterations in gene control and epigenetic
alterations are the driving forces for malignancy and its
development.96 Alterations of signaling pathways,
metabolic pathways, cytoskeleton and DNA repair pathways have been
identified to be associated with tumorigenesis and progression of
different types of cancers.97 Moreover, signaling
pathways that control cell growth, proliferation, cell specialization
and apoptosis, when damaged could lead to carcinogenesis and disease
progression.97-99 Activation of focal adhesion and
MAPK signaling pathways and subsequent dysregulating genetic processes
are further uncovered in the development of bladder
cancer.100
Data generated by RNA sequencing and bioinformatics analyses revealed
that 17 differentially expressed genes were down-regulated in 5637 cell
line whereas 44 were up-regulated in comparison to
T24.46 Similarly, down-regulation of WNT9A and WNT10A
was confirmed in both cell lines which have been found to be associated
with alteration of Wnt signaling pathways that contribute to bladder
cancer initiation and development1,9 Using RNA-Seq,
the most significantly enriched pathway involved in the development of
bladder cancer was found to be the cell adhesion molecules (CAMs)
pathway (FDR= 2.67E-08).101 Further enrichment of
bladder cancer pathway, focal adhesion, and extracellular matrix (ECM)
receptor interaction pathways revealed that genes such as PTPRF ,VEGFA and CLDN7 participated in all the pathways including
bladder cancer.101 The upregulation of genes such asITGA , F3 , ANXA1 have been reported in
cancer-related pathways associated with cell growth, cellular cycle and
apoptosis. However, downregulation of GRB7 , VEGP genes was
also noted in the same pathways.102
Further, upregulation of Interferon-g, angiogenesis, and inflammatory
pathways was observed in NEURAL, mesenchymal-like (MES), and
squamous-cell carcinoma-like (SCC).103 Nevertheless,
downregulation of several DEGs have been reported in immune activation
pathways like NF-kappa B signaling pathway, MAPK signaling pathway and
PI3K-Akt signaling pathway.104 Interleukin-10
production, lymphocyte chemotaxis and aberrant IFNγ, NF-κB and ERK
signalling networks are the major pathways identified in the immune
transcriptome related to programmed death-ligand 1 (PD- L1) inhibitors
status and may participate in the evasion of immunity in high- grade
muscle invasive urothelial carcinoma of the bladder
(HGUC).105 Similarly, PIK3/AKT/MTOR pathway is
activated by ERBB2 and FGFR3 (types of receptor tyrosine kinases) and is
found to control essential carcinogenesis stages and progression of
tumour.106 In a different study, key signaling
pathways including vascular endothelial growth factor (VEGF/VEGFR)
pathway and PI3K-Akt-mTOR pathway were identified and have been linked
to promote muscle-invasive bladder carcinoma. Also, through activation
of Janus kinase-signal transducer and activator of transcription
(JAK/STAT) signaling pathway, carcinogenesis of urothelial carcinoma was
improved by Insulin-like growth factor binding protein 4–1 (IGFBP4–1).
Upregulation of IGFBP4–1 in bladder tissue might play a significant
role in the initiation and progression of bladder
cancer.71 Similarly, L-type amino acid transporter 1
(LAT1) which transport leucine (essential amino acid) control mammalian
Target of Rapamycin (mTOR) signaling pathway and has been linked to the
initiation and progression of urothelial carcinoma.107
Interestingly, RNA-sequencing has shown significant upregulation (fold
change > 2.0) of 1793 genes, on the other hand,
downregulation of 1759 genes was recorded after knockdown of
Methyltransferase-like 3 (METTL3), suggesting that methylation of METTL3
may halt the process of N6 -methyladenosine
(m6A) methylation which could lead to progression of urothelial
carcinoma.108 The functional enrichment analysis
revealed that strong (significant) negative correlation was observed in
MYC oncogene and TNF-α/NF-κB target genes pathways while strong positive
correlation was noticed in other signaling pathways in relation to
METTL3 knockout.108
Moreover, activation of RAS pathway was observed more in all BC159-T
samples than TCGA-urothelial bladder carcinoma (TCGA- BLCA)
samples.79 The alterations of DNA in urothelial
carcinoma are controlled by the activation of the Ras–MEK–ERK and PI3
kinase–AKT–mTOR pathways either by tumour suppressor genes or
oncogenes and thus, RB1-dependent G1-S cell cycle restriction point,
anabolic metabolism, and cell survival RB1-dependent G1/S checkpoint,
cell continuity (survival) and building aspect of metabolism (anabolism)
regulate carcinogenesis through these pathways.109 In
about 20% of muscle-invasive bladder neoplasm, mutation in fibroblast
growth factor (FGFR3) was activated, triggering activation of receptor
that encourage profuse growth through downstream activation of
ERKs.109,110 Genetically altered FGFR3 (mutant FGFR3)
has been reported to activate RAS-MAPK pathway which led to abnormal
proliferation of cancer cells.106
Several attempts have been put in place to avert proliferation of cancer
cells by targeting the specific molecular pathways for the development
of bladder cancer. For example, anticancer drugs like infigratinib and
dasatinib were used to target Erk1/2 and Src signalling pathways and
thus overcome most resistance observed in cancer
cells.111 Similarly, three combination of anticancer
drugs (romidepsin + gemcitabine + cisplatin) have been used to target
the ERK pathway by increasing the level of reactive oxygen species (ROS)
which trigger cysteine-aspertic proteases (caspases) that played a vital
role in cell apoptosis.112 Therefore, understanding
integrated metabolomic and transcriptomic pathways related to bladder
cancer could offer alternative ways for the treatment of bladder
cancer.113