**6. Conclusion**

Based on studies of HBV-induced hepatocarcinogenesis (a typical evolutionary process), we put forward the theory of *Cancer Evo-Dev*. Under conditions of genetic predisposition, exogenous factors such as viral infection can induce chronic inflammation. The elimination of chronic infection can relieve inflammation, reducing the incidence of cancer and subsequently extending effective survival. As the theory describes, tumor-initiating cells obtain survival advantage during the evolutionary process of mutation-selection–adaptation by activating a "stem-ness" pathway and simultaneously causing evolutionary heterogeneity. Critical molecules in a functional subnetwork that maintains and promotes the *Cancer Evo-Dev* process can be demonstrated using systems biology approaches. The development of high-efficiency inhibitors that will target these critical molecules and block corresponding signal pathways could be a powerful treatment strategy in advanced cancers. The theory of *Cancer Evo-Dev* will serve three purposes: first, the early prevention that reduces the cancer incidence and delays its onset; second, targeted therapy that reduces morbidity and mortality rates. Therefore, this theory can contribute to the realization of "P4 pattern" medicine (predictive, preventive, personalized, and participatory).

#### **Acknowledgements**

This work was supported by grant 2015CB554006 from the National Key Basic Research Program of China, grants 91529305, 81520108021, and 81673250, and 81521091 from the National Natural Science Foundation of China.

## **Conflict of interest**

The authors declare no conflict of interest.

*Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach*
