Abstract 1 Breast cancer-associated metastasis is significantly increased in a m
ID: 19573 • Letter: A
Question
Abstract 1Breast cancer-associated metastasis is significantly increased in a
model of autoimmune arthritis
Lopamudra Das Roy,1,2 Latha B Pathangey,1 Teresa L Tinder,1,2 Jorge L Schettini,1,2 Helen E Gruber,3 and Pinku Mukherjee1,2
Breast Cancer Res. 2009; 11(4): R56.
Introduction
Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis.
Methods
To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice.
Results
We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden.
Conclusions
The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer, especially with regards to the prognosis and treatment options.
Abstract 1 Evaluation: Trace the use of the scientific method that was used in this study- include a statement of the hypothesis and an analysis of their experimental design. You do not need to know what the specific molecules called “cytokines” are – just realize that when they are made in a tissue they increase the level of inflammation.
Explanation / Answer
The hypothesis of this study was: If a site of chronic inflammation is associated with autoimmune arthritis, then there will be an increase in breast cancer tumor metastasis. This study was carried out using two test groups: one highly metastatic (4T1) and the other non-metastatic (TUBO), or the control. The results of the study indicate that there was a correlation between tumor and arthritis severity, and it was also found that metastatic breast cancer cells augment the severity of arthritis. Another finding was that treatment with anti-IL17 + celecoxib abrogated the development of metastasis and significantly reduced the primary tumor burden. There are interesting findings, however, there are several gaps in the research. First, how large were the sample sizes? How many animals were tested? There is a big difference if one animal was tested versus 10, 20, 50, etc. Second, what statistical tests were used? Since two populations were compared in this study, a chi square should be used to determine if there differences observed were statistically significant or not. Without that, the differences observed could be explained by individual differences or other circumastance.. stress could increase the immune response leading to a igher concentration fo cells at these locations. Third, how many times was this experiment repeated? Were other drugs used or just these two? And lastly, would this apply to to humans? Though it is great to find this in mice, not a single disease where a cure has been discovered in mice has been the same in humans. Though this study presents interesting and positive findings and does have a solid hypothesis, much more testing and redesigning the objectives would be necesarry. Specifically, though the hypothesis is valid, it is very broad. It would do better to look more specifically.