The heterogeneity of macrophage functions was suggested as early as the late 1990s.[26, 27] Macrophage activation can be broadly divided into the following two types: classically activated macrophages (M1), which promote inflammation, and alternatively activated macrophages (M2), which inhibit inflammation.[27, 28] Those TAMs demonstrating enhanced expression of CD163 (hemoglobin scavenger receptor), CD204 (class A macrophage scavenger receptor), CD206 (mannose receptor, C type 1), stabilin-1, arginase-1, and accelerated production of IL-10, VEGF, PGE2, and MMP9, generally show characteristics of M2 macrophages.[6-8] The proangiogenic and immunosuppressive activity in the tumor microenvironment mediated by TAMs can also be considered the result of M2 macrophage function.[6-8] Because CD163 and CD204 are specifically expressed on macrophages, and antibodies to these antigens that are suitable for immunohistochemical analysis are commercially available,[10, 29, 30] many researchers have used these molecules as markers of the M2 phenotype in both in vitro and in vivo studies. The details of the functions of these molecules remain unclear; however, a few studies have indicated that these molecules are involved either in regulating the inflammatory responses or in maintaining the protumoral functions of macrophages.[31-33] The clinicopathological studies using anti-CD163 or anti-CD204 antibodies are summarized in Table 2. In malignant lymphoma, glioma, and kidney cancer, higher CD163 expression on TAMs is associated with worse clinical prognosis, but no correlation exists between clinical prognosis and the number of CD204-expressing TAMs.[10, 34-36] In esophageal cancer, a higher number of CD204-expressing TAMs is associated with poor clinical outcome, but the number of CD163-positive TAMs is not. These observations suggest that CD163 and CD204 are not expressed in completely identical macrophage populations. In addition, the functional significance of CD163- or CD204-positive TAMs might be different among sites and histological types of cancer. We suggest that both CD163 and CD204 should be analyzed to evaluate the polarization of TAMs and that CD163- and/or CD204-positive TAMs are considered as “protumoral” macrophages/TAMs.
In a recent review, based on their location and function, Qian and Pollard classified TAMs into the following six types: angiogenic; immunosuppressive; invasive; metastasis-associated; perivascular; and activated macrophages. Not all of these macrophage types of TAMs show the phenotype of M2 macrophages. Tumor-associated macrophages with M1 characteristics have also been observed in animal models of glioma and human pancreatic cancer.[39, 40] Although the concept of “M1/M2 macrophages” is a convenient hypothesis simply dividing TAMs into two populations, we should note that TAMs contain various macrophage populations with a wide range of polarization statuses stimulated by complex signals in tumor microenvironment.