Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

Abstract

Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.

Counterintuitive production of tumor-suppressive secretomes from Oct4- and c-Myc-overexpressing tumor cells and MSCs

“…We have previously shown that overexpressing Lrp5, β-catenin, Snail, or Akt converted many types of bone cells such as mesenchymal stem cells (MSCs), osteoblasts, osteocytes, and osteoclasts into induced tumor-suppressing (iTS) cells 3 - 7 . iTS cells secrete well-known tumor-suppressing proteins such as p53 and Trail, as well as a group of uncommon tumor suppressors 3 , including Hsp90ab1, calreticulin, and peptidylprolyl isomerase B.…”

PI3K-activated MSC proteomes inhibit mammary tumors via Hsp90ab1 and Myh9

“…The anti-tumor action of CM was resistant to nuclease treatment and filtering with a 3-kD cutoff, and we thus focused on the proteomes as anti-tumor agents. 18 Since the previous work was mainly conducted using mouse cells, the question herein was whether human-derived MSCs, which have been used in regenerative medicine and can be harvested from bone marrow, 19 would be used to generate iTSCs and tumor-suppressive proteomes. We examined commercially available human MSCs, as well as adherent cells isolated from a human bone marrow aspirate-derived MSC (BMSCs).…”

Muscle and Bone Defects in Metastatic Disease

“…Similar antitumor capability was observed in MSCs generated by overexpressing LRP5, β-catenin, Snail, or Akt [203]. Activation of WNT signaling in osteoclasts, osteoblasts, and cancer cells resulted in their conversion to tumor-suppressive cells with secretomes enriched with Hsp90ab1, enolase 1 (Eno1), moesin (MSN), and ubiquitin C (Ubc), which acted as atypical tumorsuppressors [204][205][206]. Osteoclast secretome-derived Hsp90ab1 and Eno1 inhibited tumor progression by suppressing TGF-ß signaling and interacting with CD44, facilitating tumor cell killing by natural killer (NK) cells [204,207].…”

“…Activation of WNT signaling in osteoclasts, osteoblasts, and cancer cells resulted in their conversion to tumor-suppressive cells with secretomes enriched with Hsp90ab1, enolase 1 (Eno1), moesin (MSN), and ubiquitin C (Ubc), which acted as atypical tumorsuppressors [204][205][206]. Osteoclast secretome-derived Hsp90ab1 and Eno1 inhibited tumor progression by suppressing TGF-ß signaling and interacting with CD44, facilitating tumor cell killing by natural killer (NK) cells [204,207]. They also exhibited bone-protective roles as osteoclast secretome inhibited RANKL-stimulated osteoclast differentiation and stimulated osteoblast differentiation.…”