Alternatively activated macrophages are associated with metastasis and poor prognosis in prostate adenocarcinoma

Hu, Weixian; Yunjuan, Qian; Yu, Feng; Liu, Wei; Wu, Yanhua; Fang, Xiaowu; Hao, Wenke

doi:10.3892/ol.2015.3400

Cited by 62 publications

(56 citation statements)

References 35 publications

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“…In summary, the ability of DI17E6 to target integrin alpha V provides the potential to suppress PCa metastasis through a variety of mechanisms including inhibition of cell-cell and cell-extracellular matrix interactions, cellular invasion and cell signaling [23, 24]. These findings provide the rationale to perform future studies to provide in vivo validation and further insight into integrin control of prostate cancer progression and to pursue inhibition of integrin alpha V as a therapeutic target for PCa.…”

Section: Discussionmentioning

confidence: 99%

Abituzumab Targeting of αV-Class Integrins Inhibits Prostate Cancer Progression

Jiang

Dai

Yao

et al. 2017

Molecular Cancer Research

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Integrins that contain an integrin alpha V subunit contribute to multiple functions that promote cancer progression. The goal of this study was to determine if abituzumab (DI17E6, EMD 525797), a humanized monoclonal antibody (mAb) against integrin alpha V impacts, prostate cancer (PCa) progression. To evaluate this, PCa cells were treated with DI17E6 and its effects on proliferation, apoptosis, cell cycle, adhesion, detachment, migration, invasion and phosphorylation of downstream targets, including FAK, Akt and ERK were determined. DI17E6 promoted detachment and inhibited adhesion of PCa cells to several extracellular matrix (ECM) proteins and cells found in the bone microenvironment, but had no impact on cell viability, cell cycle and caspase 3/7 activity. DI17E6 inhibited migration and invasion of PCa cells. Additionally, DI7E6 decreased phosphorylation of FAK, Akt and ERK. These results indicate that inhibition of integrin alpha V with DI17E6 inhibits several pro-metastatic phenotypes of PCa cells and therefore provide a rationale for further evaluation of DI17E6 for diminishing PCa progression. Implications This work identifies that therapeutic targeting of integrins containing an alpha V integrin unit inhibits cancer progression and thus may be of clinical benefit.

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Section: Discussionmentioning

confidence: 99%

Abituzumab Targeting of αV-Class Integrins Inhibits Prostate Cancer Progression

Jiang

Dai

Yao

et al. 2017

Molecular Cancer Research

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“…In part this is attributable to the phenomenon of immunosuppression. Tumor-associated macrophages (TAMs) are among the most abundant nontransformed cell types in solid cancers (1)(2)(3)(4), and growing evidence suggests that TAMs can promote cancer progression and therapeutic resistance in a wide range of human malignancies (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). TAMs can be acutely targeted via the inhibition of colony-stimulating factor-1 (CSF1 or M-CSF) or its receptor, CSF1R (CD115), and in preclinical studies, CSF1/CSF1R inhibitors reduce tumor growth in murine tumor models (15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy

Győri¹,

Lim²,

Grant³

et al. 2018

JCI Insight

106

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Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.

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“…6 Many observations indicate that M2 macrophages have pro-tumor functions in different neoplastic tissues [7][8][9] as well as in PCa. 10,11 However, little is known with respect to how macrophages are recruited to the PCa microenvironment and differentiate into an M2 phenotype, and the underlying mechanisms controlling polarization of macrophages to an M1 or M2 phenotype remain unclear.…”

Section: Introductionmentioning

confidence: 99%

PKCζ in prostate cancer cells represses the recruitment and M2 polarization of macrophages in the prostate cancer microenvironment

Fan

Zhang

et al. 2017

Tumour Biol.

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Tumor-associated macrophages are key regulators of the complex interplay between tumor and tumor microenvironment. M2 Macrophages, one type of tumor-associated macrophages, are involved in prostate cancer growth and progression. Protein kinase C zeta has been shown to suppress prostate cancer cell growth, invasion, and metastasis as a tumor suppressor; however, its role in chemotaxis and activation of tumor-associated macrophages remains unclear. Here, we investigated the role of protein kinase C zeta of prostate cancer cells in regulation of macrophage chemotaxis and M2 phenotype activation. Immunohistochemistry was performed to analyze the expression of protein kinase C zeta and the number of CD206+ M2 macrophages in human prostate tissue. Macrophage chemotaxis and polarization were examined using Transwell migration assays and a co-culture system. Quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to detect M2 markers, protein kinase C zeta, interleukin-4, and interleukin-10 expression. We found the expression of protein kinase C zeta increased in prostate cancer tissues, especially in the early stage, and was negatively associated with tumor grade and the number of CD206+ macrophages. Inhibition of protein kinase C zeta expression in prostate cancer cells promoted chemotaxis of peripheral macrophages and acquisition of M2 phenotypic features. These results were further supported by the finding that silencing of endogenous protein kinase C zeta promoted the expression of prostate cancer cell-derived interleukin-4 and interleukin-10. These results suggest that protein kinase C zeta plays an important role in reducing infiltration of tumor-associated macrophages and activation of a pro-tumor M2 phenotype, which may constitute an important mechanism by which protein kinase C zeta represses cancer progression.

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Alternatively activated macrophages are associated with metastasis and poor prognosis in prostate adenocarcinoma

Cited by 62 publications

References 35 publications

Abituzumab Targeting of αV-Class Integrins Inhibits Prostate Cancer Progression

Abituzumab Targeting of αV-Class Integrins Inhibits Prostate Cancer Progression

Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy

PKCζ in prostate cancer cells represses the recruitment and M2 polarization of macrophages in the prostate cancer microenvironment

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