Interaction of adipocytes and cancer cells to promote breast cancer growth in CCL/CCR7 chemokine axis

Abstract

Cancer-associated adipocytes (CAAs) are one of the major components in breast cancer tumor microenvironment (TME), which were smaller, less lipids, less differential markers than normal adipocytes and had cancer promoting effects. CAAs secrete several cytokines to influence cancer cells including hormones, interleukins, and chemokines. Studies revealed that CAAs secrete CCL5 and CCL2 to promote breast cancer cells. CCL19, CCL21/CCR7 chemokine was reported to have correlation with obesity and prognosis in breast cancer patients. However, study on the expression level and functions of CCL19 and CCR7 in breast cancer is limited and the effects to prognosis in breast cancer patients was varied from different studies. Thus, we aim to evaluate the interaction between adipocytes and breast cancer cells through the CCL/CCR7 chemokine axis. In the present study, we validated that the presence of pre-adipocytes or adipocytes on cancer cell growth, migration, and tumor growth rate in xenograft model. Both CCR7 and CCL19 expressions were upregulated in the blood and tissues samples of breast cancer patients, as well as in breast cancer cell lines. Interestingly, pre-adipocytes incubated in the conditioned medium of breast cancer cells differentiated into mature adipocytes, this implicated TME has some tumor-promoting factors that induced the differentiation of pre-adipocytes into mature adipocytes. Moreover, direct co-culture of adipocytes with breast cancer cells induced dedifferentiation and EMT transition phenotypes and upregulated CCR7 expression. Knockdown of CCR7 alleviated the promoting effects of adipocytes on breast cancer cell growth and migration. Also, EMT transition was reversed upon silencing of CCR7. In conclusion, CAAs in the TME interact with breast cancer cells to promote disease progression through CCL/CCR7 axis. On the other hand, breast cancer cells modify the surrounding pre-adipocytes into more mature and invasive phenotype. The findings in this study reveal a potential anti-tumor target by blocking CCR7 to intervene the CCL/CCR7 chemokine axis in the TME thus inhibited the tumor promoting action of CAAs. This could be a new target in treating breast cancer.