Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis - PubMed (original) (raw)

Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis

Julia Hobson et al. Breast Cancer Res Treat. 2013 Jun.

Abstract

Development of metastasis in peripheral tissues is a major problem in the fight to cure breast cancer. Although it is becoming evident that chronic inflammation can contribute to tumor progression and metastasis, the effect of acute inflammation in primary tumor is less known. Using mouse models for breast cancer here we show that biopsy of mammary tumors increases the frequency of lung metastases. This effect is associated with the recruitment of inflammatory cells to the lung and elevated levels of certain cytokines such as IL-6 in the lung airways. Antiinflammatory treatment prior to and after the biopsy reduces the development of metastases triggered by the biopsy. In addition, while lack of IL-6 does not affect primary tumor development, it protects from increasing number of metastases upon biopsy. Thus, our studies show that in addition to chronic inflammation, acute immune response caused by invasive procedures in the primary tumor may cause an increased risk on peripheral metastases, but the risk could be decreased by anti-inflammatory treatments.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest

Figures

Figure 1

Figure 1. Effect of mammary tumor biopsy in tumor progression

(A) Size of the tumors that underwent biopsy (Biopsy) and control tumors (Control) over time after biopsy (n=6 mice). Tumor growth rate was slightly increased in mice undergoing biopsy (p < 0.05), as determined by random coefficient analysis with time included as a quadratic term. (B) Immunohistochemistry staining for Ki67 in tumors isolated from “Control mice” (control) and “Biopsy mice” (Biopsy) 8 days after biopsy. For “Biopsy mice”, an area distal to the biopsy and an area adjacent to the biopsy site within the same tumor are shown. 100x magnification. (C) Immunohistochemistry staining for CD45 in sections of tumors isolated from Control mice and Biopsy mice that had biopsy 2 days or 8 days prior to tissue harvesting. 100 × magnification.

Figure 2

Figure 2. Increased number of metastases in the lung upon biopsy of the mammary tumor

(A) H & E sections of lungs from Control mice and Biopsy mice 8 days after the biopsy. Micrometastases are displayed as highly dense nucleated (strong blue) spots within the parenchyma of the lung. The arrow points to representative micrometastases. 100x magnification. (B) A higher magnification (400x) of a micrometasis in the lung of Biopsy mice 8 days after biopsy, H & E staining. (C) Immunohistochemistry staining for CK8 on a metastasis in the lung of Biopsy mice 8 days after biopsy (200x magnification). (D) The number of tumor metastases in a whole lung histological section (H & E staining) from Control and Biopsy mice (n=6) 8 days after biopsy. *, denotes p <0.05, as determined by student’s t test analysis. (E) Immunohistochemistry staining for Ki67 on a metastasis in the lung of Biopsy mice 8 days after biopsy (200x magnification).

Figure 3

Figure 3. Biopsy of mammary tumors leads to a rapid inflammatory response in the lung

(A) Immunohistochemistry analysis for CD45 in sections of the lung of Biopsy mice 8 days after biopsy showing the presence of CD45 cells within a micrometastasis. 400x magnification. (B) Immunohistochemistry analysis for CD45 in lung sections of Control mice and Biopsy mice 2, 3 or 8 days after biopsy. 200x magnification. (C) Percentage of macrophages and neutrophils in BAL of Control mice and Biopsy mice (n=3) 3 days after biopsy. *, denotes p < 0.05, as determined by student’s t test analysis.

Figure 4

Figure 4. Anti-inflammatory treatment prevents the increase in lung metastases upon biopsy

(A) Tumor size at different times after biopsy in mice that received vehicle or ibuprofen (n= 4). There was a slight but statistical significant (p <0.05) decreased in tumor growth with ibuprofen as determined by random coefficient analysis with time included as a quadratic term. (B) The number of tumor metastases in a whole lung histological section (H & E staining) from Biopsy mice (8 days after biopsy) that received ibuprofen (n=5) or vehicle (n=4). *, denotes p <0.05, as determined by student’s t test. (C) Percentage of macrophages and neutrophils in BAL of Biopsy mice (3 days after biopsy) that receive ibuprofen or vehicle (n= 3). *, denotes p < 0.05, as determined by student’s t test analysis. (D) Immunohistochemistry analysis for CD45 in lung sections of Biopsy mice (3 days after biopsy) that received ibuprofen or vehicle. 200x magnification.

Figure 5

Figure 5. IL-6 contributes to the increased frequency of lung metastases caused by the biopsy of mammary tumors

(A) IL-6 production in BALF of Control mice and Biopsy mice (n=6) 3 days after biopsy. *, denotes p < 0.05, as determined by student’s t test analysis. (B) Kaplan-Meier survival curve of untreated MMTV-PyMT (WT) and IL-6 KO x MMTV-PyMT (IL6 KO) mice (n=8). p <0.05 as determined by log-rank test. (C) Number of spontaneous lung metastases in untreated MMTV-PyMT (WT) mice (n=4) and IL-6 KO x MMTV-PyMT (IL6 KO) mice (n=5). No statistically significant difference between WT and IL-6 KO mice was found (p= 0.75) as determined by student’s t test. (D) Tumor size at different times after biopsy in WT (n=4) and IL-6 KO mice (n=7). There was no statistical significant difference in tumor growth, as determined by random coefficient analysis. (E) The number of tumor metastases in a whole lung histological section (H & E staining) from WT mice (n=4) or IL-6 KO mice (n=7) 8 days after biopsy. *, denotes p <0.05, as determined by student’s t test.

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