Search for novel molecules cross-talking between muscle and cancer<br/>with therapeutic potential against cachexia and cancer

Project Information

MUSCLEANDCANCER

Grant agreement ID: 277008

Closed project

Start date 1 June 2012

End date 31 May 2016

Funded under

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Total cost € 100 000,00

EU contribution € 100 000,00

Coordinated by

ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
Italy

Final Report Summary - MUSCLEANDCANCER (Search for novel molecules cross-talking between muscle and cancerwith therapeutic potential against cachexia and cancer)

My laboratory focuses on cancer cachexia that is a very debilitating loss of muscle mass that affects up to 80% of cancer patients. Remarkably, 20-48% of cancer-related deaths are caused by respiratory failure due to loss of mass from the diaphragm muscle. No treatment is available. Anti-cachexia therapies could thus increase the survival of cancer patients. We are interested to questions like: How can we stop/delay the lethal muscle wasting associated to many forms of cancers? Why are skeletal muscles exceptionally resistant to cancers?
The address of the project public website is as follows: http://www.marionegri.it/en_US/home/research_en/dipartimenti_en/oncology/cancer_cachexia_airc_start-up
Since the beginning of the project in 2012, we have set up many in vivo cachectic models, including colon adenocarcinoma C26 and Lewis Lung Carcinoma (LLC). We have dissected from them atrophying muscles and performed gene expression analysis on them with respect to healthy muscles. Newly identified pathways are currently matter of our research activity. We have characterized the C26-bearing mice at the level of multiple tissues through sophisticated technologies, like ultrasounds-based imaging, microCT and bioluminescence-based imaging.
Targeted drugs are currently matter of our studies to test their ability to block cachexia in vivo and in vitro. In detail, we analyzed microarray datasets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents, but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the CXCR4 pathway were downregulated only in muscles atrophying because of cancer: SDF1, PAK1 and ADCY7. Notably, we found that in Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 were inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, β, γ) declined also in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anti-cachexia properties (i.e. Sunitinib that we published in OncoTarget in 2014 to be anticachectic) restored their expression. Overexpressing genes of this pathway (i.e. SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1β had increased total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed a time- and dose-dependent reduction in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (i.e. CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer. This work has been published recently on Oncogene and the European Union acknowledged accordingly.
On the other hand, we are trying to dissect at the molecular level how physical activity protects from cancers or muscle wasting associated with cancers. In particular, we are focusing on the hormonal circuits governing the crosstalk between muscle and cancers.
The disappearance of newly identified molecules in plasma and/or muscles of cancer patients due to bed-ridden state (i.e. absence of exercise) or cachexia (i.e. inflammatory state) could contribute to cancer growth and/or reduce patient survival. Drugs aimed at increasing them should be taken into consideration to improve the overall body status of such cancer patients and to extend their life.
Rosanna Piccirillo, PhD, [e-mail]