Journal Article

Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

Olaku, Oluwole, Grubb, Robert L., Bottaro, Donald P., Wong, Tiffany K., Roy, Arpita, Costello, Rene, Lee, Young H., De Silva, Dinuka M., Wright, Cara E., Lee, Molly M., Agarwal, Piyush K., Apolo, Andrea B.

2021

Overview

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amplification / Animals / Autocrine Communication / Autocrine signalling / Axl protein / Axl Receptor Tyrosine Kinase / Biology and life sciences / Bladder / Bladder cancer / Cancer / Cancer therapies / Cell activation / Cell Line, Tumor / Cell migration / Cell proliferation / Databases, Factual / Epithelial-Mesenchymal Transition - genetics / FDA approval / Gene amplification / Gene Expression Regulation, Neoplastic / Genetic aspects / Genomes / Health aspects / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Invasiveness / Kaplan-Meier Estimate / Kinases / Ligands / Medical research / Medicine and Health Sciences / Mesenchyme / Metastases / Metastasis / Mice / Muscles / Neoplasm Invasiveness / Oncology / Patients / Phenotypes / Protein-tyrosine kinase / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Proto-Oncogene Proteins - antagonists & inhibitors / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Receptor mechanisms / Receptor Protein-Tyrosine Kinases - antagonists & inhibitors / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - metabolism / Receptors / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism / Research and Analysis Methods / RNA Interference / RNA, Small Interfering - metabolism / Survival / Transcription factors / Transplantation, Heterologous / Tumors / Tyrosine / Urinary Bladder Neoplasms - metabolism / Urinary Bladder Neoplasms - mortality / Urinary Bladder Neoplasms - pathology / Urothelial carcinoma