Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSCinduced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

“…These findings suggested that LOX is one of factors responsible for EMT of cancer cells in hypoxia. Several studies examining the relationship between LOX families and EMT previously reported that inactivation of LOX by baminopropionitrile, an active site inhibitor of LOX, also inhibited the hypoxia-induced EMT of cervical cancer cells [25], and LOX induced by hypoxia was correlated with the expression of EMT markers, such as Snail [45] and Twist [46]. Furthermore, LOX-like 2 interacts with and stabilizes Snail 1, promoting CDH1 silencing, resulting in inducement of EMT [47,48].…”

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

“…For cancer cells producing a high level of IL1 such as in LoVo colon cancer cells and HCC1806 breast cancer cells, BM-MSCs are activated by tumor-derived IL1 to produce protumor factors such as PGE2 and IL6 to promote cancer progression (19). For cancer cells producing a low level of IL1, such as MDA-MB-231 (widely metastatic) and MCF7 (noninvasive) breast cancer cells, (i) hyaluronan produced by MSCs activates the CD44 pathway in cancers to induce LOX expression and promote the EMT and invasion of cancer cells (42); and (ii) TGFβ produced by cancer cells or tumor stromal cells promotes expression of protumor factors such as IL6 and SDF1 by BM-MSCs (4,38). Intriguingly, the expression of multiple genes related to these three pathways, including receptors for IL1 and TGFβ, IL6, SDF1, and the synthases of PGE2 and hyaluronan, as well as the production of PGE2 and hyaluronan, was dramatically lower in iPSC-MSCs with or without exposure to tumor microenvironment.…”

“…One essential mechanism of the protumor effects of BM-MSCs is the up-regulation of lysyl oxidase (LOX) in adjacent cancer cells by triggering the CD44-signaling pathway with hyaluronan (HA) to promote EMT and metastasis (42). Tumor necrosis factor α-induced protein 6 (TSG6), a secreted protein highly expressed by BM-MSCs (43), enhances or induces the binding of HA to cell-surface CD44 (44).…”

Mesenchymal stem cells in the tumor microenvironment

“…MSCs promoted the production of lysyl oxidase from breast cancer cells, which in turn stimulated the Twist transcription factor, which mediates the MSCs-triggered EMT of carcinoma cells. Thus, MSCs enhance metastasis of cancer cells to the lungs and bones (39). It was also reported that paracrine transforming growth factor-β1 (TGF-β1) secreted by MSCs regulated the establishment of EMT in MCF7 cells by targeting the ZEB̸miR-200 regulatory loop (40).…”