Page 16 - TD-1-1

Tumor Discovery Monocytes from single-cell analysis

angiogenic role in solid tumors . It is proposed that 3.4. Differentiation into TAMs and moDCs
[82]
CD11b Gr1 myeloid cells and CD11b VEGFR1 In tumor tissue, monocytes can be differentiated into
+
+
+
[83]
+
MDSC might also promote tumor angiogenesis. TAMs or moDCs. Nevertheless, proper classification of
[84]
+
However, human TIE2 monocytes have been reported TAMs and DCs, especially in inflamed or tumor tissue is
to belong to CD16 subsets and to exert proangiogenic still lacking .
+
[94]
activity in solid tumors in vivo . A study enrolled 168
[38]
hepatitis C virus (HCV)-infected patients including 89 3.4.1. TAMs
with hepatocellular carcinoma (HCC) and examined the TAMs comprise macrophages derived from both embryo
level of TIE2-expressing monocytes/macrophages (TEMs) and hematopoietic stem cells (HSCs) . Multiple studies
[95]
had defined TEMs as CD14 CD16 TIE2 cells in the have shown that the embryonic TAMs are responsible
+
+
+
peripheral blood and liver . for wound healing and tissue remolding, while the HSC-
[85]
Of note, we are still facing some challenges. First, derived TAMs are mainly engaged in immune inhibition
[96]
whether the pro-angiogenic function depends on and antigen-presentation . Tumor cells produce
monocytes or differentiated TAMs is unclear. Second, chemoattractants, including CSF-1, CCL2 (MCP-1), CCL3,
the relationship between circulating TIE-2 monocytes and CCL5. Then, monocytes in the circulating blood are
+
[97]
and intratumoral pro-angiogenic TAMs (including TIE- recruited into tumor tissue and differentiate into TAMs .
+
2 macrophages) has not been directly unveiled as TIE-2 Recent studies showed that TAMs promote spheroid
+
macrophages also facilitate angiogenesis, which promotes formation and tumor growth at the early stages of
tumor metastasis . transcoelomic metastasis in an established mouse model of
[86]
epithelial ovarian cancer. To be specific, epidermal growth
3.3.2. Remodeling of extracellular matrix (ECM)
factor (EGF) secreted by M2 macrophage-like TAMs
ECM is comprised of collagens, glycoproteins, and upregulated VEGF/VEGFR signaling in surrounding
proteoglycans, which nourish the tumor cellular ecosystem. tumor cells, thus promoting their proliferation and
The tumoral ECM exerts its pro-tumoral function by migration .
[98]
providing critical biomechanical and biochemical cues It has been verified in the mouse mammary tumor
that facilitate tumor cell growth, survival, invasion, and model that the tumor-monocyte pool almost exclusively
metastasis as well as by regulating angiogenesis and consisted of Ly6ChiCX3CR1 monocytes, which were
low
immune function. Besides, the tumoral ECM is an outcome enriched in tumor tissue and replenished M2-like
of aberrantly modified structural proteins and remodeling TAMs. In addition, these TAMs were suggested to
events regulated by specific proteolytic and protein cross- promote angiogenesis and inhibit T cells activation .
[22]
linking enzymes [87,88] . In tumor ECM, the physical barriers Nevertheless, studies on identifying spatially and
between cells are highly proteolytically degraded, thus functionally distinct TAM subpopulations are currently
permitting the invasion of malignant and endothelial cells lacking. In healthy tissue, blood monocytes are recruited
and promoting the activation and production of cryptic to different tissues and then, they differentiate into
proteins, which are responsible for tumor cell survival, monocyte-derived macrophages and moDCs to maintain
proliferation, motility, and the neoangiogenic switch [89,90] . homeostasis. While in tumors, monocytes can be divided
In an orthotopic CRC model, monocyte-derived into immunosuppressive TAM and monocytic MDSCs,
[99]
TAMs advance tumor development by remodeling its promoting tumor progression and immune evasion .
ECM composition and structure. To be specific, unbiased TAMs are abundant in tumor stroma both in mice
transcriptomic and proteomic analyses defined a distinct and in humans . Microenvironmental stimuli drive the
[3]
TAM-induced ECM molecular signature composed of formation of a macrophage either toward the “classic” (M1)
an ensemble of matricellular proteins and remodeling or the “alternative” (M2) activation state [100] . It is known
enzymes that they provided to the TME. The synthesis and that fully polarized M1 and M2 (or alternatively activated)
assembly of collagen types I, VI, and XIV are upregulated . macrophages are the extremes of a series of consecutive
[91]
+
Macrophages derived from CCR2 monocytes can states [101] . M1 macrophages are considered to be anti-tumor
directly degrade the ECM within tumors by endocytosing and promote immune responses. In contrast, TAMs, which
deposited collagen . Collagen introduced into the dermis display an M2-like phenotype and have high scavenging
[92]
of mice undergoes cellular endocytosis through partial ability, promote tissue repair and angiogenesis and
[4]
MMP-dependent manner and is degraded completely in facilitate tumor progression [5,102] . However, Franklin et al.
lysosomes. Collagen uptake was predominantly executed pointed out that TAMs did not express M2 markers, such
by a minor population of M2-like macrophages . as Ym1, Fizz1, and Mrc1 in mammary cancer. Instead,
[93]
Volume 1 Issue 1 (2022) 7 https://doi.org/10.36922/td.v1i1.4