TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases

Abstract

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.

A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

“…Before these studies, only ECs were thought to express the angiopoietin (1)(2)(3)(4) receptor Tie2 [25]. Nowadays, some cell types have been discovered to express Tie2: endothelial cells (ECs), TEMs, a subset of TAMs, pericyte precursors of mesenchymal origin, a subset of hematopoietic stem cells, and some cancer cell lines [26][27][28]. Two studies showed that Tie2 is expressed mainly by intermediate monocyte (CD14 + CD16 + ), whereas one study shows that Tie2 is also expressed in non-classical monocyte (CD14 dim CD16 + ).…”

SIRT7 interacts with TEK (TIE2) to promote adriamycin induced metastasis in breast cancer

“…By promoting the expression and secretion of plasmin and MMP-2, these signaling pathways trigger the migration of endothelial cells and promote tumor angiogenesis, leading to tumor growth and metastasis [37,38]. In addition, TIE2 can participate in the regulation of the dormancy process of breast cancer cells, leading to increased resistance to chemotherapeutic drugs [39]. In the current study, we found that ADR can promote EMT in breast cancer cells in vitro and is accompanied by upregulation of the vascular endothelial marker CD31 in vivo, suggesting that the metastasis induced by ADR is related to tumor angiogenesis.…”

The Mechanistic Roles of Sirtuins in Breast and Prostate Cancer

“…Furthermore, a recent study demonstrated that SIRT7 antagonizes TGF-β signaling and inhibits metastasis of breast cancer [ 81 ]. On the contrary, a more recent study revealed that SIRT7 promotes Adriamycin-induced metastasis in breast cancer by interacting with TIE2 [ 82 ], a tyrosine kinase receptor that induced the dormancy of breast cancer cells, resulting in increased resistance to chemotherapy [ 117 ]. Given the limited studies conducted to date and contradictory findings, more studies are required to provide insight into the modulation of other signaling proteins (including transcription factors) by SIRT7 causing either tumor-suppressing or tumor-promoting effects in breast cancer.…”