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Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity.

Duong MN, Cleret A, Matera EL, Chettab K, Mathé D, Valsesia-Wittmann S, Clémenceau B, Dumontet C - Breast Cancer Res. (2015)

Bottom Line: The results were validated in vivo in a mouse xenograft model.Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium.Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. mn.duong@hotmail.com.

ABSTRACT

Introduction: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes on ADCC.

Methods: We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in a mouse xenograft model.

Results: We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or degradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killer cells, but did not alter natural killer cells' cytotoxicity. Preincubation of breast cancer cells with the conditioned medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium. Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.

Conclusions: Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.

No MeSH data available.


Related in: MedlinePlus

Abdominal adipose tissue inhibits antitumor effect of trastuzumab in vivo. (A) Tumor growth in BT-474 xenograft mice treated with trastuzumab or rituximab in the presence or absence of lipoma. Median ± standard error of the mean data are shown. (B) Normalization of the tumor volumes shown in (A) with the tumor volumes of mice treated with rituximab. (C) Photos of the tumors in contact with the lipomas taken from mice treated with either trastuzumab (left) or rituximab (right). L, Lipoma; ns, Not significant; T, Tumor. **P < 0.01.
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Fig6: Abdominal adipose tissue inhibits antitumor effect of trastuzumab in vivo. (A) Tumor growth in BT-474 xenograft mice treated with trastuzumab or rituximab in the presence or absence of lipoma. Median ± standard error of the mean data are shown. (B) Normalization of the tumor volumes shown in (A) with the tumor volumes of mice treated with rituximab. (C) Photos of the tumors in contact with the lipomas taken from mice treated with either trastuzumab (left) or rituximab (right). L, Lipoma; ns, Not significant; T, Tumor. **P < 0.01.

Mentions: Our results indicate that adipose cells promote cancer resistance to trastuzumab-mediated ADCC in vitro. To understand whether adipose tissue can exert the same effect in vivo, we conducted the experiment in SCID mice, which have functional macrophages and NK cells [32]. Abdominal adipose tissue obtained from patients undergoing plastic surgery was injected subcutaneously into SCID mice to form a lipoma. BT-474 tumor was grafted next to the lipoma, and mice were treated with trastuzumab or rituximab as a control. The lipoma alone did not grow in the mice (data not shown). As shown in Figure 6A and 6B, trastuzumab inhibited the growth of BT-474 tumor in the absence of lipoma, but not in the presence of lipoma. Moreover, the interface between the lipoma and the tumor was well vascularized (Figure 6C). Therefore, our data strongly suggest that adipose tissue may have an impact on cancer resistance to trastuzumab treatment.Figure 6


Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity.

Duong MN, Cleret A, Matera EL, Chettab K, Mathé D, Valsesia-Wittmann S, Clémenceau B, Dumontet C - Breast Cancer Res. (2015)

Abdominal adipose tissue inhibits antitumor effect of trastuzumab in vivo. (A) Tumor growth in BT-474 xenograft mice treated with trastuzumab or rituximab in the presence or absence of lipoma. Median ± standard error of the mean data are shown. (B) Normalization of the tumor volumes shown in (A) with the tumor volumes of mice treated with rituximab. (C) Photos of the tumors in contact with the lipomas taken from mice treated with either trastuzumab (left) or rituximab (right). L, Lipoma; ns, Not significant; T, Tumor. **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4482271&req=5

Fig6: Abdominal adipose tissue inhibits antitumor effect of trastuzumab in vivo. (A) Tumor growth in BT-474 xenograft mice treated with trastuzumab or rituximab in the presence or absence of lipoma. Median ± standard error of the mean data are shown. (B) Normalization of the tumor volumes shown in (A) with the tumor volumes of mice treated with rituximab. (C) Photos of the tumors in contact with the lipomas taken from mice treated with either trastuzumab (left) or rituximab (right). L, Lipoma; ns, Not significant; T, Tumor. **P < 0.01.
Mentions: Our results indicate that adipose cells promote cancer resistance to trastuzumab-mediated ADCC in vitro. To understand whether adipose tissue can exert the same effect in vivo, we conducted the experiment in SCID mice, which have functional macrophages and NK cells [32]. Abdominal adipose tissue obtained from patients undergoing plastic surgery was injected subcutaneously into SCID mice to form a lipoma. BT-474 tumor was grafted next to the lipoma, and mice were treated with trastuzumab or rituximab as a control. The lipoma alone did not grow in the mice (data not shown). As shown in Figure 6A and 6B, trastuzumab inhibited the growth of BT-474 tumor in the absence of lipoma, but not in the presence of lipoma. Moreover, the interface between the lipoma and the tumor was well vascularized (Figure 6C). Therefore, our data strongly suggest that adipose tissue may have an impact on cancer resistance to trastuzumab treatment.Figure 6

Bottom Line: The results were validated in vivo in a mouse xenograft model.Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium.Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. mn.duong@hotmail.com.

ABSTRACT

Introduction: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes on ADCC.

Methods: We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in a mouse xenograft model.

Results: We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or degradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killer cells, but did not alter natural killer cells' cytotoxicity. Preincubation of breast cancer cells with the conditioned medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium. Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.

Conclusions: Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.

No MeSH data available.


Related in: MedlinePlus