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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.

SUBMITTER: Drescher F

PROVIDER: S-EPMC7226250 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Drescher Florian F Juárez Patricia P Arellano Danna L DL Serafín-Higuera Nicolás N Olvera-Rodriguez Felipe F Jiménez Samanta S Licea-Navarro Alexei F AF Fournier Pierrick Gj PG

Cancers 20200403 4

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 p ...[more]

PMID: 32260072

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Project description:This article describes the evaluation of the radiopharmaceutical (64)Cu-CB-TE2A-c(RGDyK) ((64)Cu-RGD) as an imaging agent for osteolytic bone metastases and their associated inflammation by targeting of the alpha(v)beta(3) integrin on osteoclasts and the proinflammatory cells involved at the bone metastatic site.The (64)Cu-RGD radiotracer was evaluated in the transgenic mouse expressing Tax (Tax(+)), which spontaneously develops osteolytic tumors throughout the vertebrae and hind limbs, using biodistribution studies and small-animal PET/CT. Histologic analysis was also performed on Tax(+) mouse tails, using hematoxylin and eosin and tartrate-resistant acid phosphatase to confirm the presence of osteolytic bone lesions and the presence of osteoclasts, respectively. Additionally, a proof-of-principle study was conducted with a small group of Tax(+) animals presenting with osteolytic lesions. These animals were treated with the bisphosphonate zoledronic acid and imaged with (64)Cu-RGD to determine whether this radiopharmaceutical was sensitive enough to detect a response to the bisphosphonate therapy.Biodistribution studies using (64)Cu-RGD demonstrated that Tax(+) mice between the ages of 6 and 12 mo had a greater accumulation of activity in their tail vertebrae than did the wild-type (WT) cohort (P = 0.013). Additionally, Tax(+) mice between the ages of 6 and 12 mo had significantly more tracer activity associated with their tail vertebrae than did Tax(+) mice older than 12 mo (P = 0.003), suggesting that earlier bone metastases cause an increased recruitment of alpha(v)beta(3)-expressing cells. Small-animal PET/CT with (64)Cu-RGD was conducted on Tax(+) and WT mice. On the basis of standardized uptake value analysis, Tax(+) mice had approximately 2-fold more tail-associated activity than did WT animals (P = 0.0157). Additionally, decreases in uptake were observed in the tails of Tax(+) mice after treatment with the osteoclast inhibitor zoledronic acid, and histologic analysis of Tax(+) mouse-tail vertebrae revealed the presence of Tax(+) tumor cells, osteoclasts, and proinflammatory cells within the bone microenvironment.Together, these data suggest that (64)Cu-RGD has the potential to effectively image osteolytic bone metastases and monitor the physiologic changes in the bone metastatic microenvironment after osteoclast-inhibiting bisphosphonate therapy.

Dataset Information

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

Publications

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

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