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Elucidating the Molecular and Cellular Mechanism Underlying Cancer Cachexia

He, Wei
http://rave.ohiolink.edu/etdc/view?acc_num=osu1385054981

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Cachexia is a debilitating syndrome associated with multiple chronic diseases, including cancer. It is characterized by extreme weight loss primarily due to the depletion of skeletal muscle as well as adipose tissue. In cancer, patients that suffer from cachexia are more susceptible to dose-limiting toxicity in chemotherapy . Cachexia not only diminishes the quality of life of cancer patients, but is also positively related to cancer mortality. Pancreatic and other gastrointestinal cancers exhibit the highest incidence of cancer cachexia, with one third of these patients losing more than 10% of their pre-illness body weight. Efforts to understand the mechanism underlying cancer cachexia might eventually improve the treatment outcome as well as the quality of life of these and other cancer patients. Muscle wasting in cachexia results mainly from aberrant signaling of pathways that usually maintains a balance between protein synthesis and degradation. The increase in catabolism usually associates with a decrease in anabolism including the Akt and mTOR signaling pathways. Although events as such inside the myofibers have been firmly established to take place in cancer cachexia, relatively little is known about events outside the muscle fibers, in the muscle microenvironment, and their potential significance in regulating wasting in cancer cachexia. To understand whether events in the muscle microenvironment are dysregulated in cancer cachexia, we started out this study by examining the ultrathin sections of skeletal muscle using electron microscopy. We observed an abnormal accumulation of cells in the interstitial space of cachectic muscles from tumor bearing mice. We further identified these cells as activated muscle stem cells. Using cellular and genetic approaches in murine cachexia models and muscle biopsies from cachectic patients, we describe in detail cancer cachexia is associated with an impaired regeneration program, and this is due to compromised differentiation from satellite cells, as well as other muscle resident myogenic progenitors. Our results further showed that the self-renewing transcription factor, Pax7, which under the control of classical NF-kB signaling, becomes deregulated and is responsible for the block of myogenic differentiation and promoting muscle wasting. Down regulation of NF-kB or Pax7, or overexpression of Pax7’s downstream target, MyoD, successfully rescued muscle weight loss in cancer cachexia. When examining the deregulated events in the muscle microenvironment, we also observed apoptosis activity in cachecitic muscles. Our results showed that a portion of Pax7+ muscle stem cells become TUNEL+ in response to tumor bearing. We further found that this apoptotic activity is induced by microvesicles derived from both cancer cell lines as well as cachectic serum. Mechanistically, tumor secreted microvesicles contain miR-21 that signals through TLR7 receptor on myoblasts to promote cell death. Furthermore, this apoptotic response is dependent on the activation of c-Jun N-terminal kinase (JNK) activity in muscle cells. Together, findings in this study provide new insights into the mechanisms of cachexia, highlighting the importance and relevance of events that take place in the muscle microenvironment in regulating muscle wasting in cancer cachexia.
Denis Guttridge (Advisor)
Kay Huebner (Committee Member)
Paul Martin (Committee Member)
Matthew Ringel (Committee Member)
170 p.
Biology; Cellular Biology; Genetics; Molecular Biology
Cancer cachexia; Pax7; NF-kB; muscle regeneration; microvesicles; miRNA; apoptosis; myogenic program; cachexia; C-26

Recommended Citations

Citations

  • He, W. (2013). Elucidating the Molecular and Cellular Mechanism Underlying Cancer Cachexia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385054981

    APA Style (7th edition)

  • He, Wei. Elucidating the Molecular and Cellular Mechanism Underlying Cancer Cachexia. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385054981.

    MLA Style (8th edition)

  • He, Wei. "Elucidating the Molecular and Cellular Mechanism Underlying Cancer Cachexia." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385054981

    Chicago Manual of Style (17th edition)

osu1385054981
452
© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.