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Page 6 of 17 Balakrishnan et al. J Cancer Metastasis Treat 2022;8:27 https://dx.doi.org/10.20517/2394-4722.2022.33

polarization of neutrophils toward pro-metastatic neutrophils or N2 subsets. γδT17 promotes N2 TANs in
[50]
an IL-8-, TNF-, and GM-CSF-dependent manner . In a murine model, it was found that migration of
melanoma cells was promoted by UV-induced inflammation, which stimulates angiogenesis by neutrophil
activity. This migration is directed toward the endothelial cells. This phenomenon is referred to as
“angiotrophism” .
[51]
The studies on TANs have been done mainly on murine models due to difficulty in accessing them in
humans, but, as murine neutrophils differ greatly from the human ones, an accurate depiction of their
activity is not possible. Using a humanized mouse model may serve as a great tool for this purpose. In the
case of hepatocellular carcinoma (HCC), Zhou et al. experimented with a humanized mouse model and
suggested that TANs which were CCL17 and CCL2 support tumor progression by promoting macrophage
+
+
+
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(F4/80 ) infiltration Tregs (FoxP3 ) from TME . HCC cells educated the neutrophils to skew toward an N2
[52]
phenotype via mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways.
Tumor progression was accompanied by greater tumor size, level of differentiation, and advanced
vascularization .
[52]
Tumor-associated macrophages
The origin of TAMs is described in Figure 1 for what are called monocyte-derived macrophages;
alternatively, they can arise from tissue-resident macrophages as well. This process is referred to as
“emergency myelopoiesis”. During carcinogenesis and proliferation, these tissue-resident TAMs undergo
[53]
phenotypic changes which sustain them in the tumor environment . They are the most abundant
populations of myeloid cells in tumors. There are conflicting observations in the case of TAMs, as their high
density in tumors can be associated with poor prognosis (in the case of lung, neck, and breast cancer) as
well as with improved tumor-fighting efficiency (in the case of colon and gastric cancer) [54,55] . In a study by
Badawi and colleagues on colon cancer, it was demonstrated that macrophage infiltration was significantly
higher in malignant cases than in benign polyps. Lymph node metastasis influenced high macrophage
infiltration and hypervascularity .
[56]
TAMs in tumors take on two lineages, the “M1” classical phenotype or the “M2” alternate phenotype. M1
(anti-tumorigenic) is a promoting phenotype where it promotes cancer treatment. M2 (pro-tumorigenic) is
referred to as the phenotype which interferes with cancer treatments. The markers of both phenotypes are
shown in Figure 2A. Some studies indicate that tissue-resident macrophages are sometimes more inclined
toward the M2 phenotype . M1 macrophages arise due to stimulus from IFN and TLR ligands (specifically
[53]
[57]
TLR4 ); M2 expands in response to IL4, IL13, TGFβ, and glucocorticoids. The mechanism of action of M1
macrophages in an anti-tumorigenic fashion is depicted in Figure 2A. In contrast, M2 macrophages are
more phagocytic, express higher levels of mannose and galactose receptors, and have a highly active
arginase (ARG1) pathway, which is detrimental to T cells . In addition, M2 macrophages produce CCL17,
[58]
CCL22, and CCL24, which leads to the formation of T helper 2 (Th2) or Tregs, eosinophils, and basophils
recruitment. This recruitment induces an immunosuppressive environment . It has also been shown that
[59]
[60]
additional secretion of CCL8 and IL-4 induces an invasive gene expression profile .
It is worth noting here that the M1/M2 phenotyping is an oversimplified version of the macrophage lineage.
The lineage of macrophages is a broad spectrum and is not limited to these two extremities. It has also been
seen that notch signaling is responsible for the M1/M2 polarization. M2 has decreased notch activity,
meaning that the notch signals support an M1 phenotype [61,62] . Notch signals help in the expression of IL-1β
and CCL2 to recruit TAMs, as shown by Shen et al. . Furthermore, cytokines, which are produced by
[63]
macrophages, aid in the stimulation of notch signals in tumor cells. Additionally, paracrine loops between