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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.

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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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Expression of mast cells (MCs) tryptase staining on bones. (A) Significant increase in MCs tryptase count in the bones of arthritic SKG mice challenged with 4T1 cells versus nonarthritic Balb/C mice injected with 4T1 cells (***P < 0.001) and in arthritic PyV MT mice induced with CII versus nonarthritic PyV MT mice (***P < 0.001). Significant increase in MCs tryptase also is observed in the bones of arthritic SKG mice with no tumor versus Balb/C mice with BC (*P < 0.05). Similarly, although not significant, we see the same trend in arthritic C57BL/6 mice induced with CII versus a spontaneous BC model of PyV MT mice with no arthritis. Representative images of tryptase staining in (B, C) bones taken at 400× magnification (six mice per experimental group and 10 fields per section). Brown staining represents MCs tryptase expression.
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Figure 4: Expression of mast cells (MCs) tryptase staining on bones. (A) Significant increase in MCs tryptase count in the bones of arthritic SKG mice challenged with 4T1 cells versus nonarthritic Balb/C mice injected with 4T1 cells (***P < 0.001) and in arthritic PyV MT mice induced with CII versus nonarthritic PyV MT mice (***P < 0.001). Significant increase in MCs tryptase also is observed in the bones of arthritic SKG mice with no tumor versus Balb/C mice with BC (*P < 0.05). Similarly, although not significant, we see the same trend in arthritic C57BL/6 mice induced with CII versus a spontaneous BC model of PyV MT mice with no arthritis. Representative images of tryptase staining in (B, C) bones taken at 400× magnification (six mice per experimental group and 10 fields per section). Brown staining represents MCs tryptase expression.

Mentions: We first assessed the expression of MCs in the tumor and metastatic niches (bone and lung). Tryptase is the most abundant secretory granule-derived serine contained in MCs that has been used as a marker for MC activation. In addition, tryptase has been shown to be a sensitive and specific marker for the localization of MCs in tissues [33-35]. By doing MC tryptase staining by IHC, we detected significantly higher numbers of MCs in the tumors of arthritic versus nonarthritic mice with BC (Figure 2A). We detected infiltration of MCs in the tumors of SKG versus Balb/C mice with BC (Figure 2B) and in the PyV MT mice induced with arthritis versus PyV MT mice with no arthritis (Figure 2C). We further identified significantly higher levels of MCs in the sites of metastasis: lungs (Figure 3) and bones (Figure 4) of arthritic versus nonarthritic mice in both (SKG and PyV MT) models. Thus, data suggest that an increase in MC migration and activation occurs within the tumor as well as in the metastatic niches, as indicated by the increased MC expression.


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)

Expression of mast cells (MCs) tryptase staining on bones. (A) Significant increase in MCs tryptase count in the bones of arthritic SKG mice challenged with 4T1 cells versus nonarthritic Balb/C mice injected with 4T1 cells (***P < 0.001) and in arthritic PyV MT mice induced with CII versus nonarthritic PyV MT mice (***P < 0.001). Significant increase in MCs tryptase also is observed in the bones of arthritic SKG mice with no tumor versus Balb/C mice with BC (*P < 0.05). Similarly, although not significant, we see the same trend in arthritic C57BL/6 mice induced with CII versus a spontaneous BC model of PyV MT mice with no arthritis. Representative images of tryptase staining in (B, C) bones taken at 400× magnification (six mice per experimental group and 10 fields per section). 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 4: Expression of mast cells (MCs) tryptase staining on bones. (A) Significant increase in MCs tryptase count in the bones of arthritic SKG mice challenged with 4T1 cells versus nonarthritic Balb/C mice injected with 4T1 cells (***P < 0.001) and in arthritic PyV MT mice induced with CII versus nonarthritic PyV MT mice (***P < 0.001). Significant increase in MCs tryptase also is observed in the bones of arthritic SKG mice with no tumor versus Balb/C mice with BC (*P < 0.05). Similarly, although not significant, we see the same trend in arthritic C57BL/6 mice induced with CII versus a spontaneous BC model of PyV MT mice with no arthritis. Representative images of tryptase staining in (B, C) bones taken at 400× magnification (six mice per experimental group and 10 fields per section). Brown staining represents MCs tryptase expression.
Mentions: We first assessed the expression of MCs in the tumor and metastatic niches (bone and lung). Tryptase is the most abundant secretory granule-derived serine contained in MCs that has been used as a marker for MC activation. In addition, tryptase has been shown to be a sensitive and specific marker for the localization of MCs in tissues [33-35]. By doing MC tryptase staining by IHC, we detected significantly higher numbers of MCs in the tumors of arthritic versus nonarthritic mice with BC (Figure 2A). We detected infiltration of MCs in the tumors of SKG versus Balb/C mice with BC (Figure 2B) and in the PyV MT mice induced with arthritis versus PyV MT mice with no arthritis (Figure 2C). We further identified significantly higher levels of MCs in the sites of metastasis: lungs (Figure 3) and bones (Figure 4) of arthritic versus nonarthritic mice in both (SKG and PyV MT) models. Thus, data suggest that an increase in MC migration and activation occurs within the tumor as well as in the metastatic niches, as indicated by the increased MC expression.

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