Abstract
Several lines of evidence suggest that altered adenosine deaminase (ADA) activity, especially its ADA2 iso-enzyme, is associated with malignant breast cancer (BC) development. Triple-negative breast cancer (TNBC) is currently the most challenging BC subtype due to its metastatic potential and recurrence. Herein, we analyzed the sources of ADA iso-enzymes in TNBC by investigating the effects of cell-to-cell interactions between TNBC cells, macrophages, lymphocytes, and endothelial cells. We also examined the potential relationship between ADA activity and cancer progression in TNBC patients. In vitro analyses demonstrated that the interactions of immune and endothelial cells with MDA-MB-231 triple negative BC cells modulated their extracellular adenosine metabolism pattern. However, they caused an increase in the ADA1 activity, and did not alter ADA2 activity in cancer cells. In turn, the co-culture of MDA-MB-231 cells with THP-1 monocyte/macrophages, Jurkat cells, and human lung microvascular endothelial cells (HULEC) caused the increase in ADA2 activity on THP-1 cells and ADA1 activity on Jurkat cells and HULEC. Clinical sample analysis revealed that TNBC patients had higher plasma ADA2 activities and lower ADA1/ADA2 ratio at advanced stages of cancer development than in the initial stages, while patients with hormone receptor positive, HER2 negative (HR+HER2-), and triple positive (HR+HER2+) breast cancers at the same stages showed opposite trends. TNBC patients also demonstrated positive associations between plasma ADA2 activity and pro-tumor M2 macrophage markers, as well as between ADA1 activity and endothelial dysfunction or inflammatory parameters. The analysis of TNBC patients, at 6 and 12 months following cancer treatment, did not showed significant changes in plasma ADA activities and macrophage polarization markers, which may be the cause of their therapeutic failure. We conclude that alterations in both ADA iso-enzymes can play a role in breast cancer development and progression by the modulation of extracellular adenosine-dependent pathways. Additionally, the changes in ADA2 activity that may contribute to the differentiation of macrophages into unfavorable pro-tumor M2 phenotype deserve special attention in TNBC.
Highlights
Triple-negative breast cancer (TNBC) is the most metastatic and prone to relapse type of breast cancer (BC). [1] It does not express estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2)
The dominant pathway leading to high adenosine concentration in the tumor microenvironment is the rapid extracellular phosphohydrolysis of ATP by ecto-nucleotidases, CD39, and CD73. [24,25] The termination of adenosine signaling in extracellular space is dependent on two mechanisms, adenosine uptake via nucleoside transporters and cell surface metabolism to inosine by adenosine deaminase (ADA). [26,27] It has been shown that many cancers, including breast cancer, are associated with elevated ADA activity. [18,23,28,29,30] In our previous study, we have demonstrated that immune cells, endothelial cells, and to a lesser extent cancer cells are sources of ADA1 iso-enzyme activity in breast cancer, while circulating monocytes and most probably tumor-associated macrophages are a dominant source of intra- and extracellular ADA2 activity. [23]
We have shown that ecto-total ADA activity (tADA) activity was increased on MDA-MB-231 cancer cells after the incubation with medium obtained from immune (THP-1 and Jurkat) and endothelial (HULEC) cells, while their effect on ecto-ADA2 activity was not changed
Summary
Triple-negative breast cancer (TNBC) is the most metastatic and prone to relapse type of breast cancer (BC). [1] It does not express estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). [1] It does not express estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). The histological diversity of different breast cancer types leads to the acquisition of specific features for their carcinogenesis, microenvironment, response to treatments, and clinical behavior. TNBC tumors lack ER, PR, and HER2 expression, they are not sensitive to endocrine therapy or HER2 treatment, and standardized TNBC treatment regimens are still lacking. Understanding molecular mechanisms underlying TNBC and the development of new TNBC treatment strategies have become an urgent clinical need. Adenosine deaminase (ADA, E.C.3.5.4.4) is an enzyme that catalyzes the irreversible deamination of either adenosine (Ado) or deoxyadenosine (dAdo). ADA occurs in two iso-enzymes, ADA1 and ADA2. Most human cells contain very small amounts of ADA2 and its main source is likely to be the monocyte–
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