Keith Syson Chan, Ph.D.
Scott Department of Urology
Department of Molecular and Cellular Biology
Dan L Dun Cancer Center
Ph.D.: University of Texas, GSBS M.D. Anderson Cancer Center
Postdoctoral training: Stanford University
Bladder Cancer Stem Cells in Invasion and Metastasis
Bladder cancer (BCa) is the second most common urological malignancy, which originates from the transitional epithelium that is composed of 3-6 layers of basal, intermediate and umbrella cells (Fig1). Two major subtypes of BCa exist: non-invasive (generally good prognosis) and invasive (poor prognosis) (Fig1), 15% of non-nvasive cancer will progress into invasive BCa; however, no diagnostic markers are available clinically for predicting this progression.
Recently, we prospectively isolated cancer stem cell (CSC) from human BCa, based on the expression of normal basal cell marker (Chan KS et al, PNAS 2009). Bladder CSC was defined functionally by its enriched ability to induce xenograft tumors that recapitulated the heterogeneity of the original tumor. We identified a bladder CSC gene-signature by geneChip, which possesses significant clinical value. CSC-signature effectively distinguishes invasive from non-invasive BCa, and also predicts the recurrence of a subset of non-invasive BCa.
Several projects are currently available:
(I) To examine the cell-intrinsic properties of CSCs that endows their unique ability to self-renew and to metastasize to distal sites.
a. Initial analysis of CSC signature revealed the upregulation of several proteins that are implicated in the process of invasion and metastasis. Our preliminary results revealed that a purified population of CSCs could be isolated, based on a combination of cell surface receptors. We will investigate the functional involvement of this purified CSC in invasion and metastasis, to elucidate the signaling molecules involved by biochemical approaches, gene knockdown by shRNAs and chemical inhibitors.
b. MicroRNAs (miRs) have been implicated in modulating the tumorigenic properties of cancer cells. Our preliminary results demonstrated that two miRs transcribed in a cluster were overexpressed in CSCs. Forced expression of one candidate miR in this cluster led to enhancement of the tumorigenic property of a cancer cell line. The predicted targets for these miRs are 2 tumor suppressors, when inactivated, will lead to the activation of an oncoprotein that is also implicated in the self-renewal of stem cells. We will elucidate the functional role of this miR cluster, to identify their targets and to examine their abilities in modulating self-renewal and tumorigenicity.
(II) To identify key components of the tumor microenvironment that interacts with and supports CSCs.
It is well established that alterations in the tumor microenvironment accompanies tumor progression and plays an active role in modulating tumor cell properties. Evidence demonstrated that glioblastoma CSCs resides in a vascular niche; however, the CSC niche in other solid tumors is uncharacterized.
Schematics summarizing the relevance of cancer stem cells in the pathogenesis of bladder cancer.
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
- Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill H, Presti J Jr, Chang HY, van de Rijn M, Shortliffe L, Weissman IL. (2009). Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A. Aug 18;106(33):14016-21.
- Chan KS, Sano S, Kataoka K, Abel E, Carbajal S, Beltran L, Clifford J, Peavey M, Shen J, Digiovanni J. (2008). Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis. Oncogene. Feb 14;27(8):1087-94.
- Sano S, Chan KS, Kira M, Kataoka K, Takagi S, Tarutani M, Itami S, Kiguchi K, Yokoi M, Sugasawa K, Mori T, Hanaoka F, Takeda J, DiGiovanni J. (2005). Signal transducer and activator of transcription 3 is a key regulator of keratinocyte survival and proliferation following UV irradiation. Cancer Res. Jul 1;65(13):5720-9.
- *Sano S, *Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J. (2005). Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. Jan;11(1):43-9. (*equal contribution co-authors)
- Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J. (2004). Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest. Sep;114(5):720-8.
- Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J. (2004). Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res. Apr 1;64(7):2382-9.