Das Roy Lopamudra, Curry Jennifer M, Sahraei Mahnaz, Besmer Dahlia M, Kidiyoor Amritha, Gruber Helen E, Mukherjee Pinku
Breast Cancer Res. 2013 Apr 11;15(2):R32. doi: 10.1186/bcr3412.
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.
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.
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.
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.
乳腺癌仍然是美国女性癌症相关死亡的第二大主要原因。转移不仅受恶性细胞内在基因变化的调控，还受微环境的影响，尤其是与慢性炎症相关的微环境。我们最近报道，患有自身免疫性关节炎的小鼠骨和肺转移的发生率显著增加，且与乳腺癌相关的生存率降低。在本研究中，我们评估了转移增加的潜在机制。
我们使用了两种小鼠模型；一种是患有自发性自身免疫性关节炎的小鼠（SKG小鼠），注射转移性乳腺癌细胞（4T1），另一种是患有自发性乳腺癌的小鼠（MMTV-PyV MT小鼠），注射II型胶原以诱导自身免疫性关节炎。监测肥大细胞水平和转移情况。
首先，我们证实，携带乳腺癌的关节炎小鼠骨和肺转移的发生率明显高于非关节炎对照小鼠。其次，我们发现关节炎小鼠原发肿瘤内肥大细胞的募集增加，这促进了转移。接下来，我们报告，没有任何肿瘤的关节炎小鼠骨骼和肺部的肥大细胞数量更多，这可能是关节炎小鼠中观察到的肺和骨转移增强的潜在原因。然后，我们表明，一旦肿瘤细胞在转移龛（骨骼和肺部）中聚集，它们会进一步增加龛内的肥大细胞数量，并协助增强转移。这可能主要是由于肥大细胞上存在的c-Kit受体与肿瘤细胞上表达的干细胞因子（SCF，c-kit的配体）之间的相互作用。最后，我们表明，用抗c-kit抗体靶向SCF/cKit相互作用可减少肥大细胞的分化，从而减少转移。
这是第一份表明肥大细胞不仅可能在重塑肿瘤微环境而且在重塑转移龛中发挥关键作用的报告，通过SCF/cKit相互作用促进伴有关节炎的乳腺癌的有效转移。
