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Prostate immunohistochemistry and quantification of CD68 positive cells. A: CD68 positive cells in benign prostate stroma. B: CD68 positive cells in low-grade cancer stroma. C: CD68 positive cells in high-grade prostate cancer. D: CD68 positive cells in a prostate cancer lymph node metastasis. E Quantification of CD68 positive cells per mm2 tissue area of benign and prostate cancer tissue (excluding gland lumina) is expressed as the mean ± SD; *P = 0.063.
Source publication
Tissue factor (TF) is a cell surface glycoprotein intricately related to blood coagulation and inflammation. This study was performed to investigate the role of monocyte-lineage cells in prostate cancer cell TF expression and cell invasion.
Prostate cancer cell invasion was tested with and without added peripheral blood monocytes or human monocyte-...
Contexts in source publication
Context 1
... significantly increased prostate cancer cell invasion when compared to the cancer cells cultured alone. Data expressed as mean AE SD; *P < 0.05; **P < 0.001. positive cells were found throughout the prostate tissue and within gland lumina. Increased CD68 positive cells were found in the prostate cancer tissue compared with benign prostate tissue (Fig. 5, compare panels A with B-D). The tissue CD68 count was increased in the prostate cancer stromal and epithelial tissue areas (average 145 AE 53/mm 2 ) compared with benign prostate (108 AE 31/mm 2 ; Fig. 5E and Table I). The differences between these groups did not reach statistical significance using the Mann-Whitney test (P ¼ ...
Context 2
... tissue and within gland lumina. Increased CD68 positive cells were found in the prostate cancer tissue compared with benign prostate tissue (Fig. 5, compare panels A with B-D). The tissue CD68 count was increased in the prostate cancer stromal and epithelial tissue areas (average 145 AE 53/mm 2 ) compared with benign prostate (108 AE 31/mm 2 ; Fig. 5E and Table I). The differences between these groups did not reach statistical significance using the Mann-Whitney test (P ¼ ...
Citations
... An earlier investigation by Samavedi et al used transwell-based culture systems to establish the co-culture model of articular chondrocytes and macrophages [30]. However, in such a system, it took almost 72 h for some immune cells to migrate to the bottom of the transwell system and establish communication with the underlying cellular niche [61,62]. Thus, by the time chondrocytes interacted with the macrophages (post 72 h), the immune cells had already started altering their native plasticity in the absence of IL supplementation. ...
The molecular niche of an osteoarthritic microenvironment comprises of the native chondrocytes, the circulatory immune cells, and their respective inflammatory mediators. Although, M2 macrophages infiltrate the joint tissue during osteoarthritis (OA) to initiate cartilage repair, the mechanistic crosstalk that dwells underneath is still unknown. Our study established a co-culture system of human OA chondrocytes and M2 macrophages in 3D spheroids and 3D bioprinted silk-gelatin constructs. It is already well established that Silk fibroin-gelatin bioink support chondrogenic differentiation due to upregulation in Wnt/β10 catenin pathway. Additionally, the presence of anti-inflammatory M2 macrophages significantly upregulated the expression of chondrogenic biomarkers (COL-II, ACAN) with an attenuated expression of the chondrocyte hypertrophy (COL-X), chondrocyte dedifferentiation (COL-I) and matrix catabolism (MMP-1 and MMP-13) genes even in the absence of the interleukins. Furthermore, the 3D bioprinted co-culture model displayed an upper hand in stimulating cartilage regeneration and OA inhibition than the spheroid model, underlining the role of silk fibroin-gelatin in encouraging chondrogenesis. Additionally, the 3D bioprinted silk17 gelatin constructs further supported the maintenance of stable anti-inflammatory phenotype of M2 macrophage. Thus, the direct interaction between the primary OAC and M2 macrophages in 3D context along with the release of the soluble anti-inflammatory factors by the M2 cells significantly contributed to a better understanding regarding the molecular mechanisms responsible for immune cell-mediated OA healing.
... In addition to PD-L1 upregulation, suppression of NK group 2D (NKG2D)-activating ligands (including ULBP1, ULBP2, ULBP3, MHC class I chain-related molecules A and B, MICA and MICB) may represent another way of tumor escape from NKCC [188]. Conversely, upregulation of NKG2D ligands promotes the anti-tumor activity of NK cells [189]. ...
The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.
... These TF-stimulated TAMs induced VEGF and MMP-9 expression, which could promote the invasive potential and angiogenesis (249). Furthermore, co-cultivation of TF-expressing cancer cell lines with human monocytes stimulated invasive capacity, an effect inhibited by a TF neutralizing antibody (250). In non-small cell lung cancer patients with lymph node metastasis, there are reported higher levels of monocyte TF mRNA, which correlate with overall survival (251). ...
Thrombotic complications are the second leading cause of death among oncology patients worldwide. Enhanced thrombogenesis has multiple origins and may result from a deregulation of megakaryocyte platelet production in the bone marrow, the synthesis of coagulation factors in the liver, and coagulation factor signaling upon cancer and the tumor microenvironment (TME). While a hypercoagulable state has been attributed to factors such as thrombocytosis, enhanced platelet aggregation and Tissue Factor (TF) expression on cancer cells, further reports have suggested that coagulation factors can enhance metastasis through increased endothelial-cancer cell adhesion and enhanced endothelial cell activation. Autophagy is highly associated with cancer survival as a double-edged sword, as can both inhibit and promote cancer progression. In this review, we shall dissect the crosstalk between the coagulation cascade and autophagic pathway and its possible role in metastasis and cancer-associated thrombosis formation. The signaling of the coagulation cascade through the autophagic pathway within the hematopoietic stem cells, the endothelial cell and the cancer cell are discussed. Relevant to the coagulation cascade, we also examine the role of autophagy-related pathways in cancer treatment. In this review, we aim to bring to light possible new areas of cancer investigation and elucidate strategies for future therapeutic intervention.
... 5,6 Among the inflammatory cells of the prostate, macrophages have gained attention, due to the intrinsic association between stromal macrophage density and progression of prostatic lesions, including cancer. 5,[7][8][9][10][11][12][13][14][15] Macrophages associated with pro-tumorigenic lesions, also called tumor-associated macrophages (TAM), have been recognized as a polarized M2 population. 16,17 TAM participate in the promotion of angiogenesis, remodeling of the extracellular matrix, and in the release of growth factors that contribute to cell proliferation, thus playing a role in the support of tumor growth and metastasis. ...
Background:
Prostate cancer remains one of the most common cancers in men. Macrophages are thought to be important regulators in cancers and their potential involvement in prostate cancer should not be overlooked. Therefore, the association between macrophages and the pre-tumorous changes in prostate epithelium during aging deserves further investigation.
Objectives:
We sought to investigate whether macrophages would be recruited into the prostate epithelium that display pathological lesions commonly found during aging.
Materials and methods:
Prostates of aging rats, with and without treatment with a combination of testosterone and estradiol, were examined for premalignant and malignant epithelial lesions. For comparison, prostates of castrated rats were also investigated.
Results:
Intraepithelial macrophages were found restricted to areas of premalignant and malignant lesions. An unprecedented interaction between macrophages and basal cells was observed in the aging pathological lesions. The intraepithelial macrophages were associated with autophagy, in contrast to those found after castration. In prostate lesions, the intraepithelial macrophages had TAM phenotype (CD68+/iNOS+/ CD206+/ARG+), denoting a possible involvement in cancer progression. However, M2 macrophages (CD68+/CD163+) were recruited into the epithelium after castration, possibly to phagocytize cells undergoing apoptosis.
Discussion and conclusion:
In conclusion, macrophages were recruited into the prostate epithelium and presented diverse phenotypes and morphology, consistent with changes reflected in the hormonal environment. Macrophages with the TAM phenotype were found restricted to areas of premalignant and malignant lesions in aging prostates, denoting a possible involvement in cancer progression. In contrast, M2 macrophages were found in the regressed epithelium after castration.
... It may be that TAM recruitment and infiltration contributes to PCa progression. 12,15,27,28 TAMs are one of key orchestrators of the smoldering inflammation present in the tumor microenvironment. In the majority of experimental and clinical studies, TAM levels have been associated with cancer progression. ...
Background
Tumor-associated macrophages (TAMs) and microvessel density (MVD) play an essential role for tumor progression in prostate cancer (PCa). In this study, we evaluated the association between TAMs, the infiltration with tumor angiogenesis and the response to androgen deprivation therapies (ADTs) in PCa to evaluate TAM infiltration as a predictive factor for PCa survival.
Materials and methods
Fifty-four specimens were collected and stained with CD 68 antibody to investigated TAM infiltration in tumor. Von Willebrand factor was stained to evaluate MVD around the cancer foci. We assessed the association between patient's age, preoperative serum prostate-specific antigen, pathologic Gleason sum (GS), TAM infiltration, MVD, and the response to ADT for 5 years after PCa diagnosis.
Results
The median TAM was observed in 28 (6-76)/high power field (x400). Increasing TAM correlated with increasing tumor angiogenesis (P < 0.001, r = 0.61), and the response to ADT was significantly better in patients with fewer TAMs (<28) than in patients with higher TAMs (>28) (P = 0.003). TAM infiltration was significantly higher in those with higher serum prostate-specific antigen, higher GS, and metastasis. Multivariate analysis showed that GS, ADT type, and MVD number were significant prognostic factors for response to ADT in PCa (P < 0.0001). An increased infiltration of TAM [hazards ratio (HR) = 4.47; 95% confidence interval (CI): 1.97–10.15], MVD (HR = 2.66; 95% CI: 1.27–5.61), metastatic status (HR = 2.29; 95% CI: 0.14-0.60), and prostate volume (HR = 2.19; 95% CI: 1.27–3.12) significantly correlated with shorter survival in PCa patients by univariate analysis (P < 0.05). Multivariate analyses revealed that TAM and metastatic status significantly correlated with poor overall survival.
Conclusions
TAM infiltration is associated with response to ADT and increased tumor angiogenesis in PCa. GS, ADT type, and MVD in PCa specimens are useful predictive factors for poor response to ADT. Increasing TAM and positive metastatic status were prognostic factors for a poorer survival in PCa patients.
... Depleting macrophages via gene targeted or pharmacologic approaches inhibits tumor growth in bone in animal models [99]. Moreover, CD68 (phagocytic capacity marker) positive macrophages are increased in metastatic breast and prostate cancers compared to matched primary tumors [100,101]. Research into the potential mechanism of the role of TAMs in promoting bone metastasis has uncovered that chemokine (C-C motif) ligand 2 (CCL2)-expressing breast tumor cells engage CCR2 + stromal cells of monocytic origin, including macrophages and preosteoclasts, to facilitate colonization in lung and bone [102]. Additionally, CSF-1, which is a potent chemokine for regulating proliferation and differentiation of osteoclasts, monocytes and macrophages, has also been implicated in the contribution of macrophage-driven bone metastasis [103]. ...
Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells to colonize and proliferate. In this unique immune milieu, multiple immune cells including T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils are involved in the process of bone metastasis. In this review, we will discuss the crosstalk between immune cells in bone microenvironment and their involvement with cancer cell metastasis to the bone. Furthermore, we will highlight the anti-tumoral and pro-tumoral function of each immune cell type that contributes to bone metastasis. We will end with a discussion of current therapeutic strategies aimed at sensitizing immune cells.
... Second, the peripheral monocytes could promote PCa progression. Lindholm et al. 25 showed that co-culture of PC-3, DU145, and LNCaP cells with isolated human monocytes significantly stimulated PCa cell invasion activity. ...
Increasing evidence indicates that inflammation may play important roles in tumorigenesis and progression, and an elevated peripheral monocyte count predicts a poor prognosis in various types of malignancies. Here, we evaluate the roles of peripheral monocyte count in the diagnosis and prognosis for prostate cancer in Chinese patients. A total of 1107 consecutive patients who had undergone prostate biopsy and 290 prostate cancer patients receiving androgen deprivation therapy as first-line therapy were retrospectively analyzed. The parameters were measured at the time of diagnosis. Univariate and multivariate logistic regression analyses were performed to identify the independent predictors of a positive biopsy. Patients were categorized in two groups using a cutoff point of 0.425 × 10 9 l-1 as calculated by the receiver-operating curve analysis for prognosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of monocyte count with progression-free survival, cancer-specific survival, and overall survival. Multivariate logistic regression analyses showed that monocyte count, age, prostate-specific antigen (PSA), free/total PSA, and prostate volume were independent predictors for prostate cancer. Multivariate Cox regression analyses identified an elevated monocyte count as an independent prognostic factor for worse cancer-specific survival (hazard ratio = 2.244, P < 0.05) and overall survival (hazard ratio = 1.995, P < 0.05), but not progression-free survival (P = 0.117). Our results indicated that an elevated monocyte count was an independent diagnostic biomarker for prostate cancer, and pretreatment peripheral monocyte count might play a significant role in the prognosis of prostate cancer patients treated with androgen deprivation therapy.
... The role of monocyte -lineage cells in prostate cancer cell invasion and tissue factor expression has been elucidated through a tissue factor (TF) which is a glycoprotein related to coagulation and inflammation [12]. In a co-culture study utilizing different cell lines and human peripheral blood monocytes it was demonstrated that there was a significant prostate cancer invasion. ...
Background: Recently we reported the successful in vitro cultivation of prostatic epithelial and
stromal cells from patients with benign prostatic hyperplasia and adenocarcinoma of the prostate
by liquid biopsy. In that study we noticed monocytes that were colonized by prostatic epithelial
cells; this was confirmed using a monoclonal antibody to prostate epithelial cells. We also detected
a deleterious effect exerted on the monocyte cytoplasm by a process yet to be determined.
Aim: To develop a hypothesis that will explain the significance of monocytes colonized by prostatic
epithelial cells in the pathogenesis of prostate adenocarcinoma.
Study Design: Retrospective analysis of images in the previous study.
Place and Duration: Kilimanjaro Christian Medical University College, Tumaini University, Moshi,
Tanzania. One month.
Results: We found that all monocytes viewed, without exception, contained intra-cytoplasmic
prostatic epithelial cells and most of them presented with apparent cytopathology. The
cytopathology presented as strand formation and shrinkage of monocytes. Often the loss of
integrity of monocyte cytoplasm could be arbitrarily graded as little to complete loss of cytoplasm.
Conclusion: We hypothesize that epithelial cells invade monocytes and colonize the cytoplasm.
Monocytes colonized by epithelial cells then participate in the metastatic process of the prostate
adenocarcinoma to different parts of the body. We report for the first time, a monocyte colonized by
an epithelial cell of the prostate gland. This could also be an unrecognized phenomenon with other
types of cancers.
... (92) Metastatic breast and prostate carcinoma have increased immunostaining for macrophages versus primary cancer, and in particular, increased CD68, a phagocytic capacity marker of cells infiltrating the metastatic lesion. (93,94) It is likely that these cells support tumors via known mechanisms such as angiogenesis as well as unexplored mechanisms. Macrophages have been long implicated in their proangiogenic role in supporting tumorigenesis. ...
Macrophages are present in nearly all tissues and are critical for development, homeostasis and regeneration. Resident tissue macrophages of bone, termed "osteal macrophages", are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggests a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, while macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health. This article is protected by copyright. All rights reserved.
... 45 Investigation in our group has shown that TF expression was positively correlated with prostate cancer invasion activity in several cancer cell lines and co-cultures with human monocyte lineage cells increased prostate cancer cell TF expression. 46 The prostate cancer cell invasion depended on TF expression as invasion was inhibited by anti-TF neutralizing antibodies. Clinical prostate cancer epithelium also showed increased TF expression compared with benign prostate epithelium. ...
Tumor growth and invasion are interconnected with the tumor microenvironment. Overexpression of genes that regulate cancer cell invasion by growth factors, cytokines, and lipid factors can affect cancer aggressiveness. A comparative gene expression analysis between highly invasive and low invasive cells revealed that various genes are differentially expressed in association with invasive potential. In this study, we selected variant PC-3 prostate cancer cell sublines and discovered critical molecules that contributed to their invasive potential.
The high invasive and low invasive variant PC-3 cell sublines were obtained by serial selection following Matrigel-coated Transwell invasion and were characterized by Transwell invasion, luciferase reporter assay, and Rhotekin pull-down assay. Lysophosphatidic acid (LPA) was added to the cultures to observe the response to this extracellular stimulus. The essential molecules related with cancer invasiveness were detected with Northern blotting, quantitative reverse transcription-polymerase chain reaction, and cDNA microarray.
Highly invasive PC-3 cells showed higher nuclear factor kappa B (NF-κB), activator protein 1 (AP-1) and RhoA activities than of low invasive PC-3 cells. LPA promoted cancer invasion through NF-κB, AP-1, and RhoA activities. Thrombospondin-1, interleukin-8, kallikrein 6, matrix metalloproteinase-1, and tissue factor were overexpressed in the highly invasive PC-3 variant cells and further upregulated by LPA stimulation.
The results suggest that the target molecules are involved in invasiveness of prostate cancer. These molecules may have clinical value for anti-invasion therapy by serving as biomarkers for the prediction of aggressive cancers and the detection of pharmacological inhibitors.
