Interstitial tumor-associated macrophages combined with tumor-derived colony-stimulating factor-1 and interleukin-6, a novel prognostic biomarker in non–small cell lung cancer

Pei, Baoxiang; Sun, Bingjie; Zhang, Zhen-fa; Wang, Anlei; Ren, Peng

doi:10.1016/j.jtcvs.2014.05.003

Cited by 42 publications

(36 citation statements)

References 33 publications

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“…For example, the expression of M-CSF and IL6 in non-small cell lung cancer correlates positively with infiltration of the tumor by TAMs (30). Prostaglandin E 2 and IL6 are associated with the tumor-induced differentiation of TAMs and with chemotherapy resistance (31,32).…”

Section: Discussionmentioning

confidence: 99%

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

et al. 2016

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Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. Cancer Res; 76(2); 358-69. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

et al. 2016

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“…A variety of markers (including CD68, CD163, CD204, HLA-DR, etc.) were used to identify different types of TAMs and the micro-distribution (in the tumor islet, stroma, or both) of TAMs in the tumor tissues [15–19]. However, some technical pitfalls have compromised the conclusions drawn from the previous studies, such as small sample size that limited the statistical power in revealing the implications of TAMs on the clinicopathological characteristics and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis

et al. 2016

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Tumor-associated macrophages (TAMs) are important components of cancer microenvironment. In the present study, we searched PubMed, Embase, Cochrane library and Web of Science to perform a meta-analysis of 20 studies including a total of 2,572 non-small cell lung cancer (NSCLC) patients, in order to determine the association between TAMs and NSCLC prognosis. The combined hazard ratio (HR) of 9 studies showed that the density of total CD68+ TAMs in the tumor islet and stroma was not associated with overall survival (OS) of the patients. However, the pooled HR of 4 studies showed that high density of CD68+ TAMs in the tumor islet predicted better OS, while the pooled HR of 6 studies showed that high density of CD68+ TAMs in the tumor stroma was associated with poor OS. A high islet/stroma ratio of CD68+ TAMs was associated with better OS. A high density of M1 TAMs in the tumor islet was associated with better OS, while a high density of M2 TAMs in the tumor stroma predicted poor OS. These findings suggest that, although the density of total CD68+ TAMs is not associated with OS, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC.

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“…Approximately 50% of patients with pathological stage I NSCLC die within 5 years of pulmonary resection, mainly because of distant metastasis and local recurrence. For patients with unresectable locally advanced NSCLC, treated with combined chemo-radiotherapy, the overall 5-year survival rate is 8 -17%, while the median survival of patients with metastatic disease, treated with platinum-based chemotherapy, ranges from 8 to 10 months ( Liu et al, 2014 ;Pei et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the identification of reliable biomarkers to early diagnose and monitor the progression of the disease, as well as to evaluate the efficacy of a therapeutic approach are urgently needed ( Pei et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity

Seta

Pozzi

Morganti

et al. 2014

Biological Chemistry

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Lung cancer is the second most commonly diagnosed neoplasm, and represents the leading cause of tumour death worldwide. As patients are often diagnosed at a late stage, current therapeutic strategies have limited effectiveness and the prognosis remains poor. Successful treatment depends on early diagnosis and knowledge concerning molecular mechanisms underlying lung carcinogenesis. In the present study, we focused on nicotinamide N-methyltransferase (NNMT), which is overexpressed in several malignancies. First, we analysed NNMT expression in a cohort of 36 patients with non-small cell lung cancer (NSCLC) by immunohistochemistry. Subsequently, we examined NNMT expression levels in the human lung cancer cell line A549 by Real-Time PCR, Western blot and catalytic activity assay, and evaluated the effect of NNMT knockdown on cell proliferation and anchorage-independent cell growth by MTT and soft agar colony formation assays, respectively. NSCLC displayed higher NNMT expression levels compared to both tumour-adjacent and surrounding tissue. Moreover, shRNA-mediated gene silencing of NNMT led to a significant inhibition of cell proliferation and colony formation ability on soft agar. Our results show that the downregulation of NNMT significantly reduced in vitro tumorigenicity of A549 cells and suggest that NNMT could represent an interesting molecular target for lung cancer therapy.

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Interstitial tumor-associated macrophages combined with tumor-derived colony-stimulating factor-1 and interleukin-6, a novel prognostic biomarker in non–small cell lung cancer

Abstract: The combination of CD68 plus TAMs, CSF-1, and IL-6 is very likely to be a valuable independent predictor of survival in patients with NSCLC. Perhaps co-expression of CSF-1 and IL-6 induces interstitial TAMs to shift toward the tumor-promoting phenotype.

Cited by 42 publications

References 33 publications

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis

Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity

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