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Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling.

Das Roy L, Curry JM, Sahraei M, Besmer DM, Kidiyoor A, Gruber HE, Mukherjee P - Breast Cancer Res. (2013)

Bottom Line: We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer.This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells.Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis.

Methods: We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored.

Results: First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

Conclusion: This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.

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Significant reduction in number of mast cells (MCs) (tryptase staining) in the tumor, lungs, and bones of mice treated with anti-SCF or anti-ckit antibody. (A through C) Significant reduction in number of MCs in (A) tumors (**P < 0.01; ***P < 0.001), (B) lungs (*P < 0.05; **P < 0.01), and (C) bones (*P < 0.05; **P < 0.01) of treated mice. (D through F) Representative images of MCs tryptase in (D) tumors (400×), (E) lungs (600×), and (F) bones (400× magnification) (six mice per experimental group and 10 fields per section per organ). Brown staining represents MCs tryptase expression.
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Figure 10: Significant reduction in number of mast cells (MCs) (tryptase staining) in the tumor, lungs, and bones of mice treated with anti-SCF or anti-ckit antibody. (A through C) Significant reduction in number of MCs in (A) tumors (**P < 0.01; ***P < 0.001), (B) lungs (*P < 0.05; **P < 0.01), and (C) bones (*P < 0.05; **P < 0.01) of treated mice. (D through F) Representative images of MCs tryptase in (D) tumors (400×), (E) lungs (600×), and (F) bones (400× magnification) (six mice per experimental group and 10 fields per section per organ). Brown staining represents MCs tryptase expression.

Mentions: Finally, to determine the levels of mast cells in the treated mice, we assessed the number of mast cells in the tumor, bone, and lung of treated mice. We observed a significant decrease in MC infiltration in the tumor, lungs, and bones of mice treated with anti-cKit receptor antibody (Figures 10A through C and 11A through C). Representative tryptase and toluidine staining of tumor, lung, and bone tissue sections is shown in Figures 10D through F and 11D through F, respectively. Interestingly, mice treated with anti-SCF also showed significant decrease in MC accumulation in the tumor, lung, and bone (Figure 10D(ii), E(ii), F(ii), and 11D(ii), E(ii), and 11F(ii), respectively), confirming the role of SCF in MC proliferation [10]. Taken together, these findings confirm that the decrease in metastasis in the treated groups (Figure 8) was driven by low MC accumulation.


Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling.

Das Roy L, Curry JM, Sahraei M, Besmer DM, Kidiyoor A, Gruber HE, Mukherjee P - Breast Cancer Res. (2013)

Significant reduction in number of mast cells (MCs) (tryptase staining) in the tumor, lungs, and bones of mice treated with anti-SCF or anti-ckit antibody. (A through C) Significant reduction in number of MCs in (A) tumors (**P < 0.01; ***P < 0.001), (B) lungs (*P < 0.05; **P < 0.01), and (C) bones (*P < 0.05; **P < 0.01) of treated mice. (D through F) Representative images of MCs tryptase in (D) tumors (400×), (E) lungs (600×), and (F) bones (400× magnification) (six mice per experimental group and 10 fields per section per organ). Brown staining represents MCs tryptase expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672823&req=5

Figure 10: Significant reduction in number of mast cells (MCs) (tryptase staining) in the tumor, lungs, and bones of mice treated with anti-SCF or anti-ckit antibody. (A through C) Significant reduction in number of MCs in (A) tumors (**P < 0.01; ***P < 0.001), (B) lungs (*P < 0.05; **P < 0.01), and (C) bones (*P < 0.05; **P < 0.01) of treated mice. (D through F) Representative images of MCs tryptase in (D) tumors (400×), (E) lungs (600×), and (F) bones (400× magnification) (six mice per experimental group and 10 fields per section per organ). Brown staining represents MCs tryptase expression.
Mentions: Finally, to determine the levels of mast cells in the treated mice, we assessed the number of mast cells in the tumor, bone, and lung of treated mice. We observed a significant decrease in MC infiltration in the tumor, lungs, and bones of mice treated with anti-cKit receptor antibody (Figures 10A through C and 11A through C). Representative tryptase and toluidine staining of tumor, lung, and bone tissue sections is shown in Figures 10D through F and 11D through F, respectively. Interestingly, mice treated with anti-SCF also showed significant decrease in MC accumulation in the tumor, lung, and bone (Figure 10D(ii), E(ii), F(ii), and 11D(ii), E(ii), and 11F(ii), respectively), confirming the role of SCF in MC proliferation [10]. Taken together, these findings confirm that the decrease in metastasis in the treated groups (Figure 8) was driven by low MC accumulation.

Bottom Line: We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer.This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells.Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis.

Methods: We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored.

Results: First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

Conclusion: This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.

Show MeSH
Related in: MedlinePlus