Extracellular Metabolic Energetics Can Promote Cancer Progression

 Loo, JM et al. (2015). Cell 160, 393–406

Speaker: Chih-Yu Huang (黃智裕)                     Time: 13:00-14:00, May 20, 2015

Commentator: Dr.Yao Chang (張堯)         Place: Room 601

Abstract:

Colorectal cancer is diagnosed in over a million patients a year and is also an important cause of death globally. About 70% of advanced stage patients died of liver metastasis^[1]. However, how exactly the colon cancer cells confer metabolic stress and hypoxia and successively adapt to the liver microenvironment for colonization still remains elusive. Recently, specific miRNAs have been identified to act to suppress or promote metastatic progression in diverse cancer types^[2], and miRNAs are found to accumulate in the liver^[3]. To identify whether miRNAs involve in liver metastasis, the authors screened 661 miRNAs in liver specimens from colorectal cancer patients with metastasis. They identified miR-551a and miR-483 as endogenous suppressors for liver colonization. They further demonstrated that both miRNAs can target creatine kinase brain type (CKB), which phosphorylates creatine to generate phosphocreatine, via transcriptomic profiling^[4]. Next, they observed that colon cancer cells can release CKB into extracellular space for conversion of creatines to phosphocreatine by using extracellular ATP. Then, the extracellularphosphocreatines are imported through SLC6a8, a transporter of creatine compounds, to generate ATP for colon cancer cell survival. Notably, loss of miR-551a and miR-483 and increased expression of CKB and SLC6a8 are observed in 66 clinical samples of colon cancer with liver metastasis compared with primary tumors. Moreover, the therapeutic efficacy for delivering miR-551a and miR-483 via adeno-associated virus or using a small molecule inhibitor to block CKB expression were found to be efficient in reducing colon cancer cell metastasis. In conclusion, the authors identified reduced miR-551a and miR-483 levels and increased CKB and SLC6a8 levels in colon cancer cells that metastasize to liver , and extracellular metabolite may play the role in energetic catalysis to promote metastasis. Targeting of the extracellular metabolite may provide a novel therapeutic approach for preventing metastasis from happening.

References

1.     Jemal, A et al. (2011). Global cancer statistics. CA Cancer J. Clin. 61, 69-90

2.     Tavazoie, S.F. et al. (2008). Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147-152

3.     Mingozzi, F. et al.(2011). Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat. Rev. Genet. 12, 341-355

4.     Wyss, M et al. (2000). Creatine and creatine metabolism. Physiol. Rev. 80, 1107-1213