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Cancer remains one of the leading lethal diseases worldwide. Identifying biomarkers of cancers might provide insights into the strategies for the development of novel targeted anti-cancer therapies. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) has been recently discovered as a candidate marker of cancer stem cell populations. Aberrant increased expression of Lgr5 may represent one of the most common molecular alterations in some human cancers, leading to long-term potentiation of canonical Wnt/β-catenin signaling. On the other hand, however, Lgr5-mediated suppression in canonical Wnt/β-catenin signaling has also been reported in certain cancers, such as B cell malignancies. Until now, therapeutic approaches targeting Lgr5-associated signaling axis are not yet clinically available. Increasing evidence have indicated that endogenous Lgr5 +  cell population is implicated in tumor initiation, progression, and metastasis. This review is to summarize our current knowledge about the importance of Lgr5 in cancer biology and the underlying molecular mechanisms of Lgr5-mediated tumor-promoting/suppressive activities, as well as potentially useful preventive strategies in treating tumor. Therefore, targeted therapeutic modulation of Lgr5 +  cancer cell population by targeting Wnt/β-catenin signaling through targeted drug delivery system or targeted genome editing might be promising for potential novel anti-cancer treatments. Simultaneously, combination of therapeutics targeting both Lgr5 +  and Lgr5 −  cancer cells may deserve further consideration considering the plasticity of cancer cells. Also, a more specific targeting of cancer cells using double biomarkers may be much safer and more effective for anti-cancer therapy.

Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy