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Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells.

Walter M, Liang S, Ghosh S, Hornsby PJ, Li R - Oncogene (2009)

Bottom Line: Our study also identifies cofilin-1, a known regulator of actin dynamics, as a determinant of the tumor-promoting activity of ASCs.The cofilin-1-dependent pathway affects the production of interleukin 6 (IL-6) in ASCs.Depletion of IL-6 from the ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.

ABSTRACT
Excessive adiposity has long been associated with increased incidence of breast cancer in post-menopausal women, and with increased mortality from breast cancer, regardless of the menopausal status. Although adipose tissue-derived estrogen contributes to obesity-associated risk for estrogen receptor (ER)-positive breast cancer, the estrogen-independent impact of adipose tissue on tumor invasion and progression needs to be elucidated. Here, we show that adipose stromal cells (ASCs) significantly stimulate migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identifies cofilin-1, a known regulator of actin dynamics, as a determinant of the tumor-promoting activity of ASCs. The cofilin-1-dependent pathway affects the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from the ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study uncovers a link between a cytoskeleton-based pathway in ASCs and the stromal impact on breast cancer cells.

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ASCs promote MDA-MB-231 cell invasion in a xenograft mouse modelMDA-MB-231-GFP cells either alone or with ASCs were transplanted under the renal capsule of immunodeficient mice (n=4 per treatment). The mice were sacrificed 2 weeks after transplantation. Sections were stained with a GFP-specific antibody for visualizing the GFP-expressing breast tumor cells. MDA-MB-231-GFP cells appear brown and mouse renal cells blue as a result of hematoxylin counter-staining. (A) Panels a and b show MDA-MB-231 transplanted alone, magnification x20 and x100, respectively. Panels c and d show MDA-MB-231 cells co-transplanted with ASCs. The white bars stand for 200 µm. (B) The depth of breast tumor cells invading into the mouse kidney tissue was used as a measure of invasiveness.
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Figure 2: ASCs promote MDA-MB-231 cell invasion in a xenograft mouse modelMDA-MB-231-GFP cells either alone or with ASCs were transplanted under the renal capsule of immunodeficient mice (n=4 per treatment). The mice were sacrificed 2 weeks after transplantation. Sections were stained with a GFP-specific antibody for visualizing the GFP-expressing breast tumor cells. MDA-MB-231-GFP cells appear brown and mouse renal cells blue as a result of hematoxylin counter-staining. (A) Panels a and b show MDA-MB-231 transplanted alone, magnification x20 and x100, respectively. Panels c and d show MDA-MB-231 cells co-transplanted with ASCs. The white bars stand for 200 µm. (B) The depth of breast tumor cells invading into the mouse kidney tissue was used as a measure of invasiveness.

Mentions: To validate the in vitro effect of ASCs on tumor cell behaviors, we used a renal capsule-based xenograft mouse model (Liu & Hornsby, 2007a) to investigate the impact of ASCs on tumor invasion in vivo. MDA-MB-231 cells were transplanted alone or with ASCs under the renal kidney capsule of immunodeficient mice (n=4 per treatment). Two weeks after transplantation, tumor development was evaluated by immunohistochemistry of the green fluorescent protein (GFP)-positive tumor cells in the xenograft mouse kidney tissue. As shown in panels a and b in Fig. 2A, MDA-MB-231 cells without ASCs formed a quite even front at the boundary between tumor cells and the mouse kidney tissue. In contrast, MDA-MB-231 cells that were co-transplanted with ASCs did not form a distinct boundary between the xenograft and kidney tissue (panels c and d in Fig. 2A). Rather, tumor cells in this case adopted a quite aggressive phenotype, as evidenced by invasion of finger-like protrusions plus individual tumor cells into the kidney parenchyma. To quantitate the ASC effect, the depth of the invading cell front was taken as an indicator for tumor invasiveness. There was a striking increase in the depth of invasion when ASCs were co-transplanted with the breast tumor cells (Fig. 2B). Taken together, both in vitro and in vivo findings clearly demonstrate a stimulatory effect of ASCs on the migratory behavior and invasive capability of breast cancer cells.


Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells.

Walter M, Liang S, Ghosh S, Hornsby PJ, Li R - Oncogene (2009)

ASCs promote MDA-MB-231 cell invasion in a xenograft mouse modelMDA-MB-231-GFP cells either alone or with ASCs were transplanted under the renal capsule of immunodeficient mice (n=4 per treatment). The mice were sacrificed 2 weeks after transplantation. Sections were stained with a GFP-specific antibody for visualizing the GFP-expressing breast tumor cells. MDA-MB-231-GFP cells appear brown and mouse renal cells blue as a result of hematoxylin counter-staining. (A) Panels a and b show MDA-MB-231 transplanted alone, magnification x20 and x100, respectively. Panels c and d show MDA-MB-231 cells co-transplanted with ASCs. The white bars stand for 200 µm. (B) The depth of breast tumor cells invading into the mouse kidney tissue was used as a measure of invasiveness.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2806057&req=5

Figure 2: ASCs promote MDA-MB-231 cell invasion in a xenograft mouse modelMDA-MB-231-GFP cells either alone or with ASCs were transplanted under the renal capsule of immunodeficient mice (n=4 per treatment). The mice were sacrificed 2 weeks after transplantation. Sections were stained with a GFP-specific antibody for visualizing the GFP-expressing breast tumor cells. MDA-MB-231-GFP cells appear brown and mouse renal cells blue as a result of hematoxylin counter-staining. (A) Panels a and b show MDA-MB-231 transplanted alone, magnification x20 and x100, respectively. Panels c and d show MDA-MB-231 cells co-transplanted with ASCs. The white bars stand for 200 µm. (B) The depth of breast tumor cells invading into the mouse kidney tissue was used as a measure of invasiveness.
Mentions: To validate the in vitro effect of ASCs on tumor cell behaviors, we used a renal capsule-based xenograft mouse model (Liu & Hornsby, 2007a) to investigate the impact of ASCs on tumor invasion in vivo. MDA-MB-231 cells were transplanted alone or with ASCs under the renal kidney capsule of immunodeficient mice (n=4 per treatment). Two weeks after transplantation, tumor development was evaluated by immunohistochemistry of the green fluorescent protein (GFP)-positive tumor cells in the xenograft mouse kidney tissue. As shown in panels a and b in Fig. 2A, MDA-MB-231 cells without ASCs formed a quite even front at the boundary between tumor cells and the mouse kidney tissue. In contrast, MDA-MB-231 cells that were co-transplanted with ASCs did not form a distinct boundary between the xenograft and kidney tissue (panels c and d in Fig. 2A). Rather, tumor cells in this case adopted a quite aggressive phenotype, as evidenced by invasion of finger-like protrusions plus individual tumor cells into the kidney parenchyma. To quantitate the ASC effect, the depth of the invading cell front was taken as an indicator for tumor invasiveness. There was a striking increase in the depth of invasion when ASCs were co-transplanted with the breast tumor cells (Fig. 2B). Taken together, both in vitro and in vivo findings clearly demonstrate a stimulatory effect of ASCs on the migratory behavior and invasive capability of breast cancer cells.

Bottom Line: Our study also identifies cofilin-1, a known regulator of actin dynamics, as a determinant of the tumor-promoting activity of ASCs.The cofilin-1-dependent pathway affects the production of interleukin 6 (IL-6) in ASCs.Depletion of IL-6 from the ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.

ABSTRACT
Excessive adiposity has long been associated with increased incidence of breast cancer in post-menopausal women, and with increased mortality from breast cancer, regardless of the menopausal status. Although adipose tissue-derived estrogen contributes to obesity-associated risk for estrogen receptor (ER)-positive breast cancer, the estrogen-independent impact of adipose tissue on tumor invasion and progression needs to be elucidated. Here, we show that adipose stromal cells (ASCs) significantly stimulate migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identifies cofilin-1, a known regulator of actin dynamics, as a determinant of the tumor-promoting activity of ASCs. The cofilin-1-dependent pathway affects the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from the ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study uncovers a link between a cytoskeleton-based pathway in ASCs and the stromal impact on breast cancer cells.

Show MeSH
Related in: MedlinePlus