Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes. (Cancer Res 2006; 66(2): 605-12)

https://cancerres.aacrjournals.org/content/canres/66/2/605.full.pdf

Distinct Role of Macrophages in Different Tumor Microenvironments

The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes TAM, major players in the connection between inflammation and cancer, summarize a number of functions (eg, promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0609385

Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation

During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

https://www.mdpi.com/2072-6694/6/3/1670/pdf

Tumor-associated macrophages as major players in the tumor microenvironment.

Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.

Integrins in angiogenesis and lymphangiogenesis

Following the development of the first mTOR inhibitor that successfully improves therapeutic survival in cancer, Raymond and colleagues look at how novel biomarker identification and the use of multitargeted and multimodality therapies could advance the next generation of these drugs. Mammalian target of rapamycin (mTOR) is a kinase that functions as a master switch between catabolic and anabolic metabolism and as such is a target for the design of anticancer agents. The most established mTOR inhibitors — rapamycin and its derivatives — showed long-lasting objective tumour responses in clinical trials, with CCI-779 being a first-in-class mTOR inhibitor that improved the survival of patients with advanced renal cell carcinoma. This heralded the beginning of extensive clinical programmes to further evaluate mTOR inhibitors in several tumour types. Here we review the clinical development of this drug class and look at future prospects for incorporating these agents into multitarget or multimodality strategies against cancer.

http://dipbsf.uninsubria.it/monti/BFPN%202009/mTOR2.pdf

Current development of mTOR inhibitors as anticancer agents.

Stromal cells, within and around the tumor, as well as tumor cells are both involved in angiogenesis which is an important step in tumor growth and metastasis. Among such stromal cells, macrophages are known to play various roles in tumor angiogenesis and have thus been called tumor-associated macrophages (TAMs). The TAM density, vascular endothelial growth factor (VEGF) expression and the microvessel density (MVD) were immunohistochemically evaluated in 249 paraffin-embedded sections of invasive ductal carcinoma of the breast. The TAM density and MVD were assessed as the average density of three hot spots at a magnification of x400 and x200, respectively. The TAM density showed a significant correlation with both the VEGF expression and MVD, while a significant correlation was also found between the VEGF expression and MVD. The TAM density was also associated with the nuclear grade, estrogen receptor status and MIB-1 count. Patients with a high TAM density had a significantly (p=0.0025) worse disease-free survival (DFS) prognosis than those with a low TAM density, while univariate analyses also indicated both the MVD (p<0.0001) and VEGF expression (p=0.0152) to be prognostic factors for DFS. A multivariate analysis indicated MVD (p=0.0057), as well as lymph node metastasis and the MIB-1 count, to be independently significant prognostic factors for DFS. In conclusion, the present study demonstrated a close association between TAM infiltration and both the VEGF expression and MVD. The prognostic significance of MVD was the strongest among these three factors in breast cancer. These findings suggested that the prognostic implications of TAM infiltration are due to the involvement of TAMs in tumor angiogenesis.

Macrophage infiltration and its prognostic implications in breast cancer: The relationship with VEGF expression and microvessel density

Objective: The PTEN tumor suppressor gene has been demonstrated to be inactivated in a variety of human tumors. In breast cancer, the PTEN gene mutation is not commonly found wherea

Reduced Expression of PTEN Protein and Its Prognostic Implications in Invasive Ductal Carcinoma of the Breast

BACKGROUND AND STUDY AIMS: Safe peritoneal access and gastric closure are the most important concerns in the clinical application of natural orifice transluminal endoscopic surgery (NOTES). We aimed to clarify the feasibility of a submucosal tunnel technique using endoscopic submucosal dissection (ESD) for transgastric peritoneal access and subsequent closure for NOTES. METHODS: Seven female pigs, each weighing about 40 kg were included in the study. The following procedures were performed: (i) after injection of normal saline into the submucosa, the mucosa was cut with a flex knife; (ii) the submucosal layer was dissected using an insulation-tipped electrosurgical knife to make a narrow longitudinal 50-mm submucosal tunnel; (iii) a small incision was made at the end of the tunnel and enlarged with a dilation balloon. After transgastric peritoneoscopy, the mucosal incision site was closed with clips. The following outcome measures were used: (a) evaluation of the technical feasibility of making a submucosal tunnel; (b) clinical monitoring for 7 days; (c) follow-up endoscopy and necropsy; and (d) peritoneal fluid culture. RESULTS: Natural orifice transluminal endoscopic peritoneoscopy with a submucosal tunnel was successfully carried out in all pigs. The pigs recovered well, without signs of peritonitis. Follow-up endoscopy showed healing of mucosal incision sites without open defects. Necropsy revealed no findings of peritonitis, confirming completeness of gastric closure; there was a thin scar in one pig and adhesion of the omentum in six pigs. Peritoneal fluid culture demonstrated no bacterial growth. CONCLUSIONS: The submucosal tunnel technique is feasible and effective for transgastric peritoneal access and closure.

Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study.

Angiopoietin (Ang) is a ligand for the endothelium-specific tyrosine kinase receptor Tie-2, while a shift in the Ang-1:Ang-2 expression ratio in favor of Ang-2 was found to be associated with tumor angiogenesis. In the present study, we analyzed the immunohistochemical expression of Ang-2 in a series of 198 breast cancers, in which VEGF expression and microvessel density (MVD) were previously determined. Ang-2 expression was negative in 24 (12%), positive in 50 (25%) and strongly positive in 124 (63%) of 198 cases. A significant correlation was found between Ang-2 and VEGF expressions (p=0.0004) and between Ang-2 expression and MVD (p=0.0006), while a high MVD was found in 10 (77%) of 13 tumors with a strongly positive VEGF and positive Ang-2 expression and in 40 (71%) of 56 tumors with a strongly positive VEGF and strongly positive Ang-2 expression. Although there was no difference in the disease free survival (DFS) stratified according to Ang-2 expression alone, the 69 patients with a strongly positive VEGF and a strongly positive or positive Ang-2 expression had a significantly (p=0.0316) worse DFS than those with other combinations of VEGF and Ang-2 expressions. A multivariate analysis indicated lymph node metastasis and MVD to be independently significant prognostic factors for DFS, while the combination of VEGF and Ang-2 expressions was not a significant factor for DFS. In conclusion, the Ang-2 expression was found to be closely correlated with VEGF expression and MVD in breast cancer, while a high MVD was frequently found in tumors with a high expression of both VEGF and Ang-2. The survival analysis demonstrated a high MVD, which was induced by a high expression of both VEGF and Ang-2, to therefore have a strong prognostic significance in breast cancer.

Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density.

https://www.giejournal.org/article/S0016-5107(11)01982-1/pdf

Kosuke Suzuki

Papers

Macrophage infiltration and its prognostic implications in breast cancer: The relationship with VEGF expression and microvessel density

Reduced Expression of PTEN Protein and Its Prognostic Implications in Invasive Ductal Carcinoma of the Breast

Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study.

Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density.

Sodium alginate as an ideal submucosal injection material for endoscopic submucosal resection: preliminary experimental and clinical study.