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Pathology 430/827
Bladder cancerEtiology, classification, and diversity
David M. Berman, MD, PhDPathology and Molecular MedicineQueen’s Cancer Research [email protected]
Objectives
1. Recognize who gets bladder cancer and why2. Recognize different types of bladder cancers
A. Two genomic pathways cause bladder cancerB. Bladder cancers can change (“progress”) over
timeI. GradeII. Stage
Objectives
1. Recognize who gets bladder cancer and why2. Recognize different types of bladder cancers
A. Two genomic pathways cause bladder cancerB. Bladder cancers can change (“progress”) over time
I. GradeII. Stage
3. Understand concept of epithelial differentiation and how it produces different types of bladder cancer cells
Epidemiology
• 4th most common cancer in men, – Affecting ~3% of men in Western countries– 3x less frequent in women– Peak age 75yrs
Recurrence
• Up to 70% of cases recur.• Estimated $3 billion annually U.S.,
– Biggest expense = surveillance (cystoscopies).
Uroplakins form permeability barrier
Min G et al. J Cell Sci 2003;116:4087-4094
©2003 by The Company of Biologists Ltd
Differentiation in urothelial carcinoma
Three cell layers of benign urothelium
He X et al., 2009 Stem Cells, 27:1487
Uroplakins
Basal cells repopulate
Superficial cells protect
Intermediate cells mature
Bladder Cancer Staging
STAGE Primary tumour (T) Regional Lymph Nodes (N) Distant Metastasis (M)
0 Ta or Tis 0 0
I T1 0 0
II T2 0 0
III T3 or T4a 0 0
IV T4b AND/OR N1-N3 AND/OR M1
Two Pathways
Urothelial Hyperplasia
Flat CIS
PUNLMPLG Papillary UrCa
Superficial inv. Muscle inv. UrCa
H-RAS/FGFR3 Activation
P53/RB Inactivation
Normal Urothelium
Papillary/Noninvasive
Flat/Invasive
Loss of CDKN2A
Non-invasive Invasive
•Urobasal A (Lund) ~ Luminal (Texas) ~ Group B (TCGA)
• Urobasal B (Sweden)
• Squamous-like (Sweden) , Basal (Texas)
Molecular Subtypes
Epithelial differentiation in cancer
Epigenetic changes
Epigenetic changes
(Basal cell)
Intermediate Cell
Urothelial differentiation inUrothelial Carcinoma Xenografts
BenignUrothelium
SW780 Cell LineXenograft
67 Kd Laminin Receptor: Surface marker of tumor “basal cells”
But not in vitro
He X et al., 2009 Stem Cells, 27:1487
SW780 Human Bladder cancer xenograft
Single cell digest
FACS
Inject 10 sites, 2-20k cells each
67LR+ (13%)
67LR+
67LR_
CK17
CK1767LR- (87%)
67LR expression in vivo identifies basal-like bladder cancer cells
He X et al., 2009 Stem Cells, 27:1487
“Basal” cells form tumors. More differentiated cells do not
67 LR bright (Basal)
Unfractionated
67 LR dim (Differentiated)
He X et al., 2009 Stem Cells, 27:1487
Gene Expression Programs in Basal-like Urothelial Cancer Cells
Migration
Angiogenesis
Apoptosis Proliferation
Signaling pathways•Jak-STAT•Notch•FAK•mTOR •EGFR•Wnt •TGF beta
67LR+
67LR_
CK17
CK17
He X et al., 2009 Stem Cells, 27:1487