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Bladder Tumor Subtype Commitment Occurs in Carcinoma In Situ Driven by Key Signaling Pathways Including ECM Remodeling.
- Source :
-
Cancer research [Cancer Res] 2021 Mar 15; Vol. 81 (6), pp. 1552-1566. Date of Electronic Publication: 2021 Jan 20. - Publication Year :
- 2021
-
Abstract
- Basal and luminal subtypes of invasive bladder tumors have significant prognostic and predictive impacts for patients. However, it remains unclear whether tumor subtype commitment occurs in noninvasive urothelial lesions or in carcinoma in situ (CIS) and which gene pathways are important for bladder tumor progression. To understand the timing of this commitment, we used gene expression and protein analysis to create a global overview of 36 separate tissues excised from a whole bladder encompassing urothelium, noninvasive urothelial lesions, CIS, and invasive carcinomas. Additionally investigated were matched CIS, noninvasive urothelial lesions, and muscle-invasive bladder cancers (MIBC) from 22 patients. The final stage of subtype commitment to either a luminal or basal MIBC occurred at the CIS transition. For all tissues combined, hierarchical clustering of subtype gene expression revealed three subtypes: "luminal," "basal," and a "luminal p53-/extracellular matrix (ECM)-like" phenotype of ECM-related genes enriched in tumor-associated urothelium, noninvasive urothelial lesions, and CIS, but rarely invasive, carcinomas. A separate cohort of normal urothelium from noncancer patients showed significantly lower expression of ECM-related genes compared with tumor-associated urothelium, noninvasive urothelial lesions, and CIS. A PanCancer Progression Panel of 681 genes unveiled pathways specific for the luminal p53-/ECM-like cluster, for example, ECM remodeling, angiogenesis, epithelial-to-mesenchymal transition, cellular discohesion, cell motility involved in tumor progression, and cell proliferation and oncogenic ERBB2/ERBB3 signaling for invasive carcinomas. In conclusion, this study provides insights into bladder cancer subtype commitment and associated signaling pathways, which could help predict therapy response and enhance our understanding of therapy resistance. SIGNIFICANCE: This study demonstrates that CIS is the stage of commitment for determining MIBC tumor subtype, which is relevant for patient prognosis and therapy response.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Administration, Intravesical
Aged
Aged, 80 and over
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
BCG Vaccine pharmacology
BCG Vaccine therapeutic use
Biomarkers, Tumor analysis
Biomarkers, Tumor genetics
Carcinoma in Situ genetics
Carcinoma in Situ pathology
Carcinoma in Situ therapy
Carcinoma, Transitional Cell genetics
Carcinoma, Transitional Cell pathology
Carcinoma, Transitional Cell therapy
Chemotherapy, Adjuvant methods
Cystectomy
Drug Resistance, Neoplasm genetics
Epithelial-Mesenchymal Transition drug effects
Epithelial-Mesenchymal Transition genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Muscle, Smooth pathology
Neoadjuvant Therapy methods
Neoplasm Invasiveness pathology
Neoplasm Invasiveness prevention & control
Neoplasm Staging
Prognosis
RNA-Seq
Receptor, ErbB-2 metabolism
Receptor, ErbB-3 metabolism
Signal Transduction drug effects
Signal Transduction genetics
Urinary Bladder cytology
Urinary Bladder surgery
Urinary Bladder Neoplasms genetics
Urinary Bladder Neoplasms pathology
Urinary Bladder Neoplasms therapy
Urothelium cytology
Whole Genome Sequencing
Carcinoma in Situ diagnosis
Carcinoma, Transitional Cell diagnosis
Extracellular Matrix pathology
Urinary Bladder pathology
Urinary Bladder Neoplasms diagnosis
Urothelium pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33472889
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-2336