Cancer Stem Cells Promote Tumor Neovascularization

Tumor growth and metastasis depend on neovascularisation, which has been recently believed promoted by cancer stem cells (CSCs), a special subpopulation of tumor cells. The cancer stem cell theory can be traced back to the first mention by Furth and Kahn in 1937, when their results revealed a single leukaemic cell capable of transmitting the systemic disease in mice [1]. However, it was not until the 1990s that CSCs were identified and wellcharacterized in acute myeloid leukaemia (AML). Among cancer cells isolated from AML patients, only a small fraction of them exhibiting the hematopoietic stem cell surface phenotype, i.e. CD34+ and CD38-, were capable of initiating leukaemia in mice similar to that of the original patient. These cells were then known as SCID leukemia-initiating cells with potentials to self-renew, proliferate and differentiate in vivo [2, 3]. Since then, CSCs from various types of cancer such as breast cancer and malignant glioma have been well characterized, and then the existence of CSCs in solid tumors has been gradually accepted [4-10]. The studies promote a common recognition of the accurate definition for CSCs reached by an American Association for Cancer Research (AACR) workshop in 2006, that CSCs are a small subset within a cancer that constitute a reservoir of self-sustaining cells with the exclusive abilities to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor [11]. Investigation on CSCs provides a new insight into our understanding for tumorigenesis, recurrence and metastasis of cancer as well as development of new strategies for cancer treatment. Due to up-regulation of drug resistance and anti-apoptotic genes as well as greater DNA-repair responses, CSCs are more resistant to chemoand/or radiotherapies than differentiated cancer cells [12-17]. Recent studies suggest that CSCs existing in the tumor are highly invasive, indicating their crucial role in invasion and metastasis of cancer [18]. Therefore, eradication of CSCs is of great importance in preventing cancer recurrence and metastasis. The increasing awareness of neovascularization holding a master switch of tumor development and progression indicates that vascularization plays a crucial role in the stage of tumor progression [19]. It is generally thought that vascularization is initiated by microenvironmental changes such as hypoxia followed by tumor outgrowing its blood