Biomedical Engineering Reference
In-Depth Information
4 Signaling Pathways Important in Prostate CSCs . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.1 Wnt/b-Catenin Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.2 Hedgehog Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.3 Notch Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.4 Nanog, Oct3/4, and Sox2 Transcriptional Network . . . . . . . . . . . . . . . . . . .
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5 Targeting of CSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.1 Targeting ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.2 Targeting the Sonic Hedgehog Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.3 Targeting the Notch Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.4 Targeting the Niche of Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.5 Targeting Stem Cell Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7 List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 Introduction
1.1 Prostate Cancer and Treatment
Prostate cancer is the leading cancer diagnosis in men in the United States, with
218,890 new cases and 27,050 deaths estimated by the American Cancer Society
for 2007 (American Cancer Society 2007). Environmental factors undoubtedly
play a key role in the genesis of prostate cancer. Asians, for example, have a
higher risk of prostate cancer after they immigrate to North America and adopt
a Western diet (Whittemore et al. 1995). Hereditary factors also play an impor-
tant part. Germline mutations in genes such as RNASEL predispose indivi-
duals to a hereditary form of prostate cancer (Casey et al. 2002). Furthermore,
multiple genetic polymorphisms with ill-defined functions have a role in the risk
of prostate cancer and are additive in risk when they are acquired in combina-
tion (Zheng et al. 2008). Therefore, as with most cancers, the events that lead to
prostate carcinogenesis are a complex mixture of factors with contributions
from hereditary and environmental components (Nelson et al. 2003).
In the development of prostate cancer, androgens, specifically testosterone
and the more potent dihydroxytestosterone, are critical and an increase in
androgen signaling occurs in the transition from benign prostate to prostate
cancer precursors (Tomlins et al. 2007). Prostate cancer is thought to arise from
the high-grade pre-neoplastic lesion, prostatic intra-epithelial neoplasia
(HPIN). The most convincing evidence for this is that genetic alterations pre-
sent within prostate cancer are often present within HPIN, supporting this
hypothesis (reviewed in Nupponen and Visakorpi 2000; Hughes et al. 2006).
Furthermore, recent evidence suggests that most of the expression changes
accompanying prostate cancer actually occur during the transition from benign
epithelium to HPIN and not HPIN to prostate cancer (Tomlins et al. 2007).
HPIN is defined pathologically by the appearance of atypical cells lining the
architecturally benign ducts and acini. The diagnosis of prostate cancer relies on
the pathological examination of a biopsy of the gland. The microscopic
