Other angiogenic factors released by TAMs include basic fibroblast growth factor, thymidine phosphorylase, urokinase-type plasminogen activator and adrenomedullin (65-67). recruitment, survival, and differentiation within the tumor site. Monocyte chemoattractant protein-1 (MCP1, also known as CCL2) is a tumor- and stromal-derived factor involved in monocyte recruitment (51). Inhibition of the CCL2-CCR2 signaling in a mouse model of breast cancer impaired monocyte infiltration, inhibited metastasis, reduced tumor growth, and depletion of tumor-derived CCL2 inhibited metastatic seeding IOWH032 (52). Next to CCL2, tumor cells secrete high levels of the growth factor colony stimulating factor-1 (CSF-1), which is involved in recruitment and differentiation of monocytes (53-55). CSF-1 programs monocyte-derived macrophages towards an pro-tumorigenic phenotype coupled to fatty ARMD5 acid oxidation (FAO) upregulation (56) and secretion of pro-tumorigenic and immunosuppressive factors such as epidermal growth factor (EGF) (57) and IL-10 (58). Hypoxia Hypoxia has been shown to induce infiltration of TAMs and reprogramming of macrophages toward the pro-tumorigenic phenotype (59-63), promoting tumor cell proliferation and chemoresistance (64). Under hypoxic conditions, TAMs produce angiogenic factors such as vascular endothelial growth factor (VEGFA). VEGFA stimulates chemotaxis of endothelial cells and macrophages (65). Other angiogenic factors released by TAMs include basic fibroblast growth factor, thymidine phosphorylase, urokinase-type plasminogen activator and adrenomedullin (65-67). Macrophages also promote angiogenesis by physically assisting sprouting blood vessels to augment the complexity of the intra-tumorigenic vascular network (68). Interestingly, under hypoxic conditions, TAMs upregulate REDD1 (regulated in development and DNA damage responses 1), a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis, leaving more glucose for neighboring cells and curtails their excessive angiogenic response, resulting in abnormal blood vessel formation (69). Lactate Extracellular lactate, secreted by tumor cells, functions as signaling molecule which leads the induction of an angiogenic response (70-73). Accumulation of extracellular lactate stimulates the programming of macrophages IOWH032 towards a pro-tumorigenic phenotype and induces expression of VEGF (74-77). Furthermore, the secretion of lactate into the stroma via MCT1 is co-transported with H+, leading to further acidification of the TME. Interestingly, recent animal studies have shown that differences in function of MCT1 transporter on melanoma cells confer different metastatic potential to these cells. The results suggest that the bidirectional, more efficient handling of lactate by the tumor cells results in a more efficient handling of the oxidative stress and may contribute to the higher metastatic potential in melanomas (78). Interestingly, acidification of the TME enhances an IL-4 driven phenotype in macrophages and induces a pro-tumor phenotype IOWH032 (79). Autophagy Another process involved in differentiation of macrophages into TAMs is autophagy (80,81). It was found that autophagy, induced by toll-like receptor 2 (TLR2) signaling, could differentiate bone marrow-derived macrophages into a pro-tumorigenic phenotype in the presence of hepatoma tumor cell condition medium (82). In another study, myeloid-cell specific autophagy was shown to impair anti-tumorigenic immune responses and promote the survival and accumulation of pro-tumorigenic macrophages in tumor tissues, a process modulated via CSF-1 and transforming growth factor (TGF) (83). Wen show that tumor cell-released autophagosomes differentiated macrophages into an immunosuppressive phenotype characterized by the expression of programmed cell death protein ligand-1 (PD-L1) and IL-10 (84). Importantly, the effects of metabolic effects of cancer cells on TAMs is not unidirectional. TAMs secrete multiple cytokines with metabolic functions, including IL-6, tumor necrosis factor alpha (TNF) and CCL18 (85-87). TAM-derived IL-6, TNF and CCL18 promote tumor cell glycolysis and proliferation (85-87). Effects of local and systemic therapies on the cross-talk between tumor cells and TAMs and their metabolic reprogramming Different local and systemic cancer therapies influence the composition of the TME and the cross-talk between the cellular components of the TME. Some of these effects can be attributed to changes of the metabolic characteristics of the TME through induction of ischemia and hypoxia or through direct effects of these drugs on the cellular metabolism or other intracellular signaling pathways (leads to.Despite the numerous studies, using metformin in clinical trials provided conflicting data (142,143). tumor-derived and TAM-derived factors and the intrinsic adaptation of the cellular metabolism of both cells to the metabolically unfavorable TME. Chemokines Tumor-derived factors are involved in monocyte recruitment, survival, and differentiation within the tumor site. Monocyte chemoattractant protein-1 (MCP1, also known as CCL2) is a tumor- and stromal-derived factor involved in monocyte recruitment (51). Inhibition of the IOWH032 CCL2-CCR2 signaling in a mouse model of breast cancer impaired monocyte infiltration, inhibited metastasis, reduced tumor growth, and depletion of tumor-derived CCL2 inhibited metastatic seeding (52). Next to CCL2, tumor cells secrete high levels of the growth factor colony stimulating factor-1 (CSF-1), which is involved in recruitment and differentiation of monocytes (53-55). CSF-1 programs monocyte-derived macrophages towards an pro-tumorigenic phenotype coupled to fatty acid oxidation (FAO) upregulation (56) and secretion of pro-tumorigenic and immunosuppressive factors such as epidermal growth factor (EGF) (57) and IL-10 (58). Hypoxia Hypoxia has been shown to induce infiltration of TAMs and reprogramming of macrophages toward the pro-tumorigenic phenotype (59-63), promoting tumor cell proliferation and chemoresistance (64). Under hypoxic conditions, TAMs produce angiogenic factors such as vascular endothelial growth factor (VEGFA). VEGFA stimulates chemotaxis of endothelial cells and macrophages (65). Other angiogenic factors released by TAMs include basic fibroblast growth factor, thymidine phosphorylase, urokinase-type plasminogen activator and adrenomedullin (65-67). Macrophages also promote angiogenesis by physically assisting sprouting blood vessels to augment the complexity of the intra-tumorigenic vascular network (68). Interestingly, under hypoxic conditions, TAMs upregulate REDD1 (regulated in development and DNA damage responses 1), a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis, leaving more glucose for neighboring cells and curtails their excessive angiogenic response, resulting in abnormal blood vessel formation (69). Lactate Extracellular lactate, secreted by tumor cells, functions as signaling molecule which leads the induction of an angiogenic response (70-73). Accumulation of extracellular lactate stimulates the programming of macrophages towards a pro-tumorigenic phenotype and induces expression of VEGF (74-77). Furthermore, the secretion of lactate into the stroma via MCT1 is co-transported with H+, leading to further acidification of the TME. Interestingly, recent animal studies have shown that differences in function of MCT1 transporter on melanoma cells confer different metastatic potential to these cells. The results suggest that the bidirectional, more efficient handling of lactate by the tumor cells results in a more efficient handling of the oxidative stress and may contribute to the higher metastatic potential in melanomas (78). Interestingly, acidification of the TME enhances an IL-4 driven phenotype in macrophages and induces a pro-tumor phenotype (79). Autophagy Another process involved in differentiation of macrophages into TAMs is definitely autophagy (80,81). It was found that autophagy, induced by toll-like receptor 2 (TLR2) signaling, could differentiate bone marrow-derived macrophages into a pro-tumorigenic phenotype in the presence of hepatoma tumor cell condition medium (82). In another study, myeloid-cell specific autophagy was shown to impair anti-tumorigenic immune reactions and promote the survival and build up of pro-tumorigenic macrophages in tumor cells, a process modulated via CSF-1 and transforming growth element (TGF) (83). Wen display that tumor cell-released autophagosomes differentiated macrophages into an immunosuppressive phenotype characterized by the manifestation of programmed cell death protein ligand-1 (PD-L1) and IL-10 (84). Importantly, the effects of metabolic effects of malignancy cells on TAMs is not unidirectional. TAMs secrete multiple cytokines with metabolic functions, including IL-6, tumor necrosis element alpha (TNF) and CCL18 (85-87). TAM-derived IL-6, TNF and CCL18 promote tumor cell glycolysis and proliferation (85-87). Effects of local and systemic therapies within the cross-talk between tumor cells and TAMs and their metabolic reprogramming Different local and systemic malignancy therapies influence the composition of the TME and the cross-talk between the cellular components of the TME. Some of these effects can be attributed to changes of the metabolic characteristics of the TME through induction of ischemia and hypoxia or through direct effects of these medicines on the cellular metabolism or additional intracellular signaling pathways (prospects to beneficial effects such as, decreased TAM infiltration, tumor growth inhibition, prevention of tumor metastasis and a decrease of pro-tumorigenic cytokines (97). Furthermore, Etoposide, a topoisomerase II-inhibitor, raises malignancy cell apoptosis in cells co-cultured with IFN-/LPS induced macrophages, but reduces apoptosis in the presence of IL-4/IL-13 induced macrophages (126). Retinoic acid (RA) altered the ability of monocytes to contribute in the tumor angiogenesis process and decreased the ability of TAMs to.