Pathophysiology of tumor-associated macrophages.
The macrophage is an important component of the human immune defense mechanism. Cancer cells secrete a variety of chemoattractants that attract macrophages and cause them to accumulate in the tumor tissue, wherein the macrophage becomes a tumor-associated macrophage (TAM). Recent evidence has shown that the function of tumor stromal TAMs can be modified by cancer cells and the factors they secrete. TAMs are directed toward stimulating tumor growth and progression and thus have protumorigenesis activity. However, there is also limited evidence that TAMs still play an important role in the killing and destruction of cancer cells, inhibit cancer metastasis, and have antitumor activity. Whether TAMs show protumorigenesis or antitumor activity depends on interaction with cancer cells, other stromal cells, and the tumor microenvironment. Gene expression profiles of TAMs, cancer cells, and other stromal cells are altered by cell-cell interactions. This phenomenon results in positive or negative regulation of angiogenesis, tumor cell proliferation, apoptosis, cancer cell migration and invasion, and the secretion of a variety of cytokines or factors. Whether TAMs have a positive or negative effect also depends on the macrophage activation state, the status of tumor development, and the anatomic locus of macrophage infiltration. Understanding of the mechanisms that regulate TAM function is essential in designing therapies to promote antitumor activity in humans. Although limited evidence from both animal and human studies indicates a potential role for TAMs in cancer treatment, the clinical usefulness of these therapies require further studies.