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LGR5 – Mediator of Tumorigenicity in Breast Cancer Stem Cells?

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Review of “LGR5 Promotes Breast Cancer Progression and Maintains Stem-Like Cells through Activation of Wnt/β-Catenin Signaling” from Stem Cells by Stuart P. Atkinson

Cancer stem cells are thought to be at the very root of most, if not all, cancers, mediating initiation, metastasis, recurrence, and drug resistance (3, 4). Understanding the molecular mechanisms which control cancer stem cells is not only important for the treatment of cancer but also in the design of therapies which do not affect “normal” tissue resident stem cells.

LGR5 (or GPR49) is expressed in multiple adult stem cell [1, 2] and over-expressed in cancer stem cell populations [3], such as in the breast, and researchers from the group of Xiaoming Xie (Sun Yat-sen University Cancer Center, Guangzhou, China) have sought to understand the fine detail behind LGR5 function in breast cancer. In a new study, published in Stem Cells, they provide evidence that LGR5 overexpression promotes tumorigenesis in breast cancer stem cells through the Wnt/β-catenin signaling pathway and highlight this as a potentially druggable anti-cancer target [4].

Expression analysis of breast cancer tumors compared to adjacent non-tumor tissues found that LGR5 over-expression occurred in around 50% of samples, and this correlated to recurrent, metastatic, aggressive tumors, and predicted poor overall survival and disease-free survival rates. This gave the researchers their first evidence that LGR5 may be oncogenic, and could be affecting breast CSCs.

To further examine the link between LGR5 and tumorigenicity, the authors generated breast cancer cell lines either stably over-expressing LGR5 or stable LGR5 KO cell lines. In vitro analysis demonstrated that LGR5 gives a growth advantage to the breast cancer stem cells and also boosted their invasive nature, while in vivo analysis found that after injection into nude mice, LGR5 over-expressing cells formed larger and heavier tumors. Furthermore, these mice also presented with large numbers of lung metastasis as compared to LGR5 KO cells.

Enrichment of breast CSCs from patient tumor samples using 3D non-adherent tumorsphere growth conditions then demonstrated that 90% of CD44high/CD24low CSCs expressed LGR5, suggesting that the tumor promoting effects of LGR5 affect the CSC compartment, or that LGR5 expression can induce a stem cell state in breast cancer cells. LGR5Hi cells sorted from breast cancer clinical specimens also formed larger more homogenous spheroids as compared to LGR5Low cells, and were more tumorigenic following injection into nude mice, suggesting again that LGR5 can confer enhanced self-renewing capacity on breast cancer cells.

So how does LGR5 potentiate tumorigenicity? Interestingly, LGR5 over-expressing breast cancer cells had a protein expression pattern which correlated to an epithelial-mesenchymal transition (EMT), which is known to enable mobility, and the group showed that this EMT was induced via LGR5 acting through the Wnt signaling pathway. Correlating to this link, Wnt3a addition induced the expansion of tumorspheres from LGR5high cells, while the Wnt agonist Dkk1 did the opposite. Finally, breast cancer patient samples with LGR5 expression were positively correlated to expression of key molecules in the Wnt/β-catenin pathway (β-catenin, cyclinD1, and C-myc).

The data presented now suggests an important link between LGR5 and increased Wnt/β-catenin pathway activity in breast cancer leading and to the promotion of aggressive tumorigenic characteristics in the cancer stem cell compartment. Why LGR5 becomes overexpressed is surely a question which needs to be answered, as its importance has been laid clear. This will hopefully provide a basis for a therapeutic intervention, although the fact that only 50% of breast cancer tissue samples expressed LGR5 also suggests that other mechanisms which boost tumorigenicity remain to be uncovered.

References

  1. Rios AC, Fu NY, Lindeman GJ, et al. In situ identification of bipotent stem cells in the mammary gland. Nature 2014;506:322-327.
  2. Lim J and Thiery JP Epithelial-mesenchymal transitions: insights from development. Development 2012;139:3471-3486.
  3. Oskarsson T, Acharyya S, Zhang XH, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 2011;17:867-874.
  4. Yang L, Tang H, Kong Y, et al. LGR5 Promotes Breast Cancer Progression and Maintains Stem-Like Cells Through Activation of Wnt/beta-Catenin Signaling. Stem Cells 2015;33:2913-2924.