Abstract
The tumor microenvironment (TME) is shaped by cancer and noncancerous cells, the extracellular matrix, soluble factors, and blood vessels. Interactions between the cells, matrix, soluble factors, and blood vessels generate this complex heterogeneous microenvironment. The TME may be metabolically beneficial or unbeneficial for tumor growth, it may favor or not favor a productive immune response against tumor cells, or it may even favor conditions suited to hijacking the immune system for benefitting tumor growth. Soluble factors relevant for TME include oxygen, reactive oxygen species (ROS), ATP, Ca2+, H+, growth factors, or cytokines. Ca2+ plays a prominent role in the TME because its concentration is directly linked to cancer cell proliferation, apoptosis, or migration but also to immune cell function. Stromal-interaction molecules (STIM)-activated Orai channels are major Ca2+ entry channels in cancer cells and immune cells, they are upregulated in many tumors, and they are strongly regulated by ROS. Thus, STIM and Orai are interesting candidates to regulate cancer cell fate in the TME. In this review, we summarize the current knowledge about the function of ROS and STIM/Orai in cancer cells; discuss their interdependencies; and propose new hypotheses how TME, ROS, and Orai channels influence each other.
Highlights
The tumor microenvironment (TME) (Figure 1) has a significant influence on carcinogenesis
The metabolism of different cell types, cell–cell interactions, the architecture of TME formed by remodeling of ECM proteins, and the blood supply together create an environment composed of oxygen; nutrients; reactive oxygen species (ROS); reactive nitrogen species (RNS); ATP; Ca2+, H+, and other ions; growth factors; chemokines; cytokines; or waste products (Figure 1)
In addition to the ROS-TME interactions outline above, which have received a lot of attention in research, Orai channels are a relatively novel ROS target (Figure 5) but may play an important role in integrating Ca2+ and ROS signaling in the TME
Summary
The tumor microenvironment (TME) (Figure 1) has a significant influence on carcinogenesis (tumor development). The metabolism of different cell types, cell–cell interactions, the architecture of TME formed by remodeling of ECM proteins (which create a stiff fibrotic matrix), and the blood supply together create an environment composed of oxygen; nutrients; reactive oxygen species (ROS); reactive nitrogen species (RNS); ATP; Ca2+ , H+ , and other ions; growth factors; chemokines; cytokines; or waste products (Figure 1). This environment, together with locally secreted molecules from different cells, leads to pH gradients, differences in oxygen tension, and interstitial pressure across the tumor [2,4,21]. Since malignant cell functions depend on Ca2+ flux, considerable interest has emerged in the therapeutic potential of inhibiting Orai for many cancer types
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