Publication Date

2012-08-03

Availability

Embargoed

Embargo Period

2013-08-02

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2012-06-04

First Committee Member

Xiang-Xi (Mike) Xu

Second Committee Member

Teresa A. Zimmers

Third Committee Member

David J. Robbins

Fourth Committee Member

Leonidas Koniaris

Fifth Committee Member

Carlos T. Moraes

Abstract

Cancer cachexia, defined by severe weight loss with inflammation, is responsible for one third of all cancer deaths. Inflammatory cytokines have been linked to muscle atrophy in cancer cachexia, but the underlying molecular mechanisms are still not fully understood. Sonic hedgehog (Shh) signaling is known to regulate embryonic muscle development and muscle regeneration. We show here, in vitro and in vivo, that cancer and cancer-related cytokines functionally activated Shh signaling in muscle cells. Activation or inhibition of Shh signaling led to muscle atrophy or muscle hypertrophy, respectively. Mechanistically, Shh signaling promoted self-renewal of selected myogenic progenitors in atrophied muscle, preventing muscle differentiation. These results suggest a unifying mechanism for chronic muscle wasting in cancer cachexia. In addition, GDC-0449, a recently FDA approved Shh pathway inhibitor, preserved body weight and reduced muscle and fat wasting in a mouse model of cancer cachexia. Thus the Shh pathway is involved in adult muscle turnover and represents a novel, rapid way forward to clinically treat muscle wasting caused by chronic diseases such as cancer.

Keywords

Sonic hedgehog; Cancer cachexia; Muscle wasting; Satellite cells; Inflammatory cytokines; GDC-0449

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