Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers

Reviewer #1 (Public review):

Summary:

Systemic and partial Tcf7l2 repression is effective in protecting cancer mice from cachexia-induced death. Hence, this is a promising treatment strategy for cancer patients suffering from cachexia.

Strengths:

The method is well-designed and clearly explained.

Weaknesses:

(1) Abbreviations should be mentioned in full terms for the first time.

(2) Relatively old or even very old references in the Introduction and Discussion.

(3) The result section contains discussion with references, as well.

(4) The number of mice in individual groups is relatively small (3 mice in some groups).

Reviewer #2 (Public review):

Summary:

This study by Leong and colleagues examines the role of the TCF7L2 transcription factor in the Wnt signaling pathway as a regulator of colon/small intestinal cancers and cachexia. Investigators utilize a Tet off repressor genetic system in mice under Dox regulation to silence TCF7L2. Results show DSS-treated APCMin/+ mice lose body weight that can be rapidly rescued by Dox treatment and suppression of TCF7L2 expression. Reduction of TCF7L2 rescues features of cachexia, including body weight, gastrocnemius muscle and adipose mass, as well as molecular markers of cachexia such as the E3 Ub ligases, MuRF1, and Atrogin-1. The most significant finding in the study is that loss of TCF7L2 reduces but does not eliminate tumor progression, as tumors go from adenomas to adenocarcinomas over time while mice are treated with Dox, yet cachexia persists. This implies that TCF7L2 has a direct effect on cachexia. Overall, the study provides insight into the role of TCFL2 in the development of intestinal cancers and muscle atrophy in cachexia.

Strengths:

The study uses an elegant genetic mouse model to provide significant new insight into the role of TCFL2 in colon and small intestinal cancers. In addition, the authors describe the role of TCF7L2 as a regulator of muscle wasting in cachexia. This, too, can be viewed as a new finding for the cachexia field.

Weaknesses:

However, in its current form, the study lacks sufficient data to support the authors' claim regarding the relevance of TCF7L2 as a regulator of cachexia.