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Dysregulation of the Wnt Pathway in Solid Tumors

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Targeting the Wnt Pathway in Cancer

Abstract

Activation of the WNT signaling pathway has long been implicated in driving cancer pathogenesis from compelling evidence derived from complementary in vitro and animal studies. Moreover, there are extensive data supporting the nuclear localization of β-catenin, a surrogate marker frequently used as a read-out of WNT pathway activation, in addition to the overexpression of pathway activators and loss of pathway inhibitors in human cancers. Despite being most often linked with colorectal cancer, WNT pathway activation has now been associated with virtually every type of solid cancer that occurs in humans, although the frequency can vary dramatically among tumor subtypes and specific pathway components. These findings have significant implications regarding the mechanisms by which pathway activation might drive tumor development in specific tumor subtypes as well as the potential utility and impact of targeting this pathway therapeutically. In this chapter, we will summarize, both by tumor type and pathway components, the expansive evidence suggesting that the pathway is dysregulated in nearly half of all the most common types of human malignancies.

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Abbreviations

APC:

Adenomatous polyposis coli

BCC:

Basal cell carcinoma

CNS:

Central nervous system

CtBP:

c-Terminal binding protein

DKK:

Dickkopf

DVL:

Disheveled

EBV:

Epstein-Barr virus

ESCC:

Esophageal squamous cell carcinoma

FAP:

Familial adenomatous polyposis

FVPC:

Follicular variant of papillary carcinoma

FZD:

Frizzled

GSK3β:

Glycogen synthase kinase 3 beta

HCC:

Hepatocellular carcinomas

HNSCC:

Head and neck squamous cell carcinoma

LEF-1:

Leukemia enhancer-binding factor 1

L-FLAC:

Low-grade adenocarcinoma of the fetal type

LOH:

Loss of heterozygosity

LRP:

Lipoprotein receptor-related protein

LTR:

Long terminal repeat

MCR:

Mutation cluster region

MMTV:

Mouse mammary tumor virus

MSI:

Microsatellite instability

NKD:

Naked cuticle homolog

NSCLC:

Non-small cell lung cancer

OEA:

Ovarian endometrial adenocarcinoma

PanIN:

Pancreatic intraepithelial neoplasia

PNET:

Primitive neuroectodermal tumor

PSA:

Prostate-specific antigen

PTC:

Parathyroid carcinoma

SFRP:

Secreted frizzled-related protein

TCF:

T-cell factor

WDFA:

Well-differentiated fetal adenocarcinoma

Wg:

Wingless

WIF-1:

WNT inhibitory factor 1

WT 1:

Wilms’ tumor 1

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Acknowledgments

The authors acknowledge that this was an ambitious task to summarize WNT pathway dysregulation in human cancer and apologize to those investigators whose work was inadvertently omitted from this review of the literature. Work in the senior authors’ laboratory has been funded by an American Cancer Society Research Scholar Grant (04-251-01-CCG), an AACR/Komen Career Development Award, and the University of Chicago Breast Cancer SPORE. J.R.P. is funded by an American Cancer Society Postdoctoral Fellowship, and H.H.L. is funded by grants from NIH/NIAMS and the Orthopaedic Research and Education Foundation.

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    Kathleen H. Goss

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  1. Jenifer R. Prosperi
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  2. Hue H. Luu
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  1. Medical Center, Dept. Surgery, University of Chicago, S. Maryland Ave. 5841, Chicago, 60637-5026, Illinois, USA

    Kathleen H. Goss

  2. Eli & Edythe Broad Center for, Regenerative Medicine &, University of Southern California, San Pablo Street 1501, Los Angeles, 90033, California, USA

    Michael Kahn

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Prosperi, J.R., Luu, H.H., Goss, K.H. (2011). Dysregulation of the Wnt Pathway in Solid Tumors. In: Goss, K., Kahn, M. (eds) Targeting the Wnt Pathway in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8023-6_5

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