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Cancer Manag Res. 2018 Mar 20;10:545-555. doi: 10.2147/CMAR.S142650. eCollection 2018.

Mechanical ventilation promotes lung metastasis in experimental 4T1 breast cancer lung-metastasized models.

Author information

1
Division of Breast and Endocrine Surgery, Department of Surgery, Borås Hospital, Borås.
2
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
3
Department of Biochemistry and Molecular Biology, China-Japan Friendship Hospital, Beijing, People's Republic of China.
#
Contributed equally

Abstract

Background/purpose:

The aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment.

Materials and methods:

In Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin-eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM).

Results:

MV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung (P<0.01). Immunohistochemical results showed increased infiltration of CD68-positive macrophages within injured lung parenchyma and metastatic tumor as well as increased expression of EpCAM in metastatic nodules. Postoperative metastases were more prevalent in the mechanically ventilated mice group compared to the non-ventilated group (P<0.05).

Conclusion:

MV-induced lung metastasis occurs by attracting circulating tumor cells to the site of the lung injury and by accelerating the proliferation of preexisting micro-metastases in the lung. These observations indicate that the metastasis-enhancing effect of MV should be considered in general anesthesia during cancer surgery.

KEYWORDS:

4T1; EpCAM; breast cancer metastasis; inflammatory cellular response; mechanical ventilation; surgery

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

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