CD68

Gene Summary

Gene:CD68; CD68 molecule
Aliases: GP110, LAMP4, SCARD1
Location:17p13.1
Summary:This gene encodes a 110-kD transmembrane glycoprotein that is highly expressed by human monocytes and tissue macrophages. It is a member of the lysosomal/endosomal-associated membrane glycoprotein (LAMP) family. The protein primarily localizes to lysosomes and endosomes with a smaller fraction circulating to the cell surface. It is a type I integral membrane protein with a heavily glycosylated extracellular domain and binds to tissue- and organ-specific lectins or selectins. The protein is also a member of the scavenger receptor family. Scavenger receptors typically function to clear cellular debris, promote phagocytosis, and mediate the recruitment and activation of macrophages. Alternative splicing results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:macrosialin
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Surveys and Questionnaires
  • TIMP1
  • Breast Cancer
  • Brain Tumours
  • Lung Cancer
  • Karyotyping
  • Immunophenotyping
  • Mutation
  • Skin Cancer
  • Macrophages
  • Transforming Growth Factor beta
  • Antigens, Differentiation, Myelomonocytic
  • Spleen
  • Adenocarcinoma
  • Neoplasm Proteins
  • Cell Proliferation
  • Brain Tumours
  • Immunoenzyme Techniques
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Muramidase
  • Staining and Labeling
  • Gene Rearrangement
  • Gene Expression Profiling
  • Adolescents
  • Pancreatic Cancer
  • Hodgkin Lymphoma
  • In Situ Hybridization
  • Biomarkers, Tumor
  • FISH
  • Staging
  • Chromosome 17
  • CD Antigens
  • Lymph Nodes
  • Cancer DNA
  • Childhood Cancer
  • Messenger RNA
  • Gene Expression
  • Receptors, Antigen, T-Cell, alpha-beta
  • Cancer Gene Expression Regulation
  • beta 2-Microglobulin
  • Melanoma
  • T-Cell Antigen Receptors
  • Immunohistochemistry
  • Differential Diagnosis
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD68 (cancer-related)

Song JX, Dian ZJ, Wen Y, et al.
Assessment of the Number and Phenotype of Macrophages in the Human BMB Samples of CML.
Biomed Res Int. 2016; 2016:8086398 [PubMed] Free Access to Full Article Related Publications
Macrophages have emerged as a key player in tumor biology. However, their number and phenotype in human bone marrow of biopsy (BMB) samples of chronic myeloid leukemia (CML) and their association with disease progression from an initial chronic phase (CP) to accelerated phase (AP) to advanced blast phase (BP) are still unclear. BMB samples from 127 CML patients and 30 patients with iron-deficiency anemia (IDA) as control group were analyzed by immunohistochemistry. The expression levels of CD68, CD163, and CD206 in BMB samples of CML patients were significantly higher than those in the patients of control group (P < 0.01), and we observed that their positive expression was gradually elevated during the transformation of CML-CP to AP to BP (P < 0.01). However, the expressions of CD68, CD163, and CD206 in released group were downregulated and contrasted to these in control group; there exists statistical significance (P < 0.01). The percentage ratio of CD163 and CD206 to CD68 was pronounced to be increasing from CML-CP to AP to BP (P < 0.01). Hence, the higher proportion of CD68(+), CD163(+) and CD206(+) macrophages in BMB samples can be considered a key factor for disease progression of CML patients. Targeting macrophages, especially the M2 phenotype may help in designing therapeutic strategies for CML.

Fan Y, Xu LL, Shi CY, et al.
MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma.
Sci Rep. 2016; 6:22793 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454-overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC.

Tewari BN, Singh Baghel K, Tripathi C, et al.
A study on local expression of NF-κB, CCL2 and their involvement in intratumoral macrophage infiltration in breast cancer.
Cell Mol Biol (Noisy-le-grand). 2016; 62(2):116-25 [PubMed] Related Publications
NF-κB has been implicated in mechanisms promoting inflammation in tumor microenvironment leading to breast cancer metastasis. Owing to critical role of CCL2 during metastasis, particularly in its capacity to act as a chemoattractant for macrophages and their precursors i.e monocytes, we decided to explore if pro-metastatic function of NF-κB could be attributable to CCL2 and/or macrophage infiltration. Through our study we provide experimental and clinical evidence in support of co-ordinated expression of chemokines CCL2, NF-κB and intratumoral macrophage content particularly with respect to breast cancer, with an additional evidence of these three variables being key determinant for poor prognosis and diminished survival amongst breast cancer patients both independently as well in a coordinated manner. The mean fold increase in mRNA expression level of NF-κB and CCL2 indicated that it was over expressed 13.57 and 13.18 fold respectively in tumor tissue as compared to adjacent normal tissue. Among these Immunohistochemistry expression of CD68 marker showed that 62 patients (66.7%) had low/moderate CD68 expression while 31 patients (33.3%) had strong expression. All three variables viz.NF-κB, CCL2 and CD68 showed significant (p<0.05 or p<0.01 or p<0.001) respectively associations with both clinicopathological (except CD68 with stage) and hormone receptors (ER, PR and Her2/neu) and their co-expressions indicating these as predictors of breast cancer. In this study we decipher the possible molecular mechanism by way of which NF-κB may promote breast cancer metastasis. Our study has clinical relevance as it establishes significance of these three variables as potential predictive markers to be employed in breast cancer.

Huang FJ, Zhou XY, Ye L, et al.
Follicular thyroid carcinoma but not adenoma recruits tumor-associated macrophages by releasing CCL15.
BMC Cancer. 2016; 16:98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The differential diagnosis of follicular thyroid carcinoma (FTC) and follicular adenoma (FA) before surgery is a clinical challenge. Many efforts have been made but most focusing on tumor cells, while the roles of tumor associated macrophages (TAMs) remained unclear in FTC. Here we analyzed the differences between TAMs in FTC and those in FA.
METHODS: We first analyzed the density of TAMs by CD68 immunostaining in 59 histologically confirmed FTCs and 47 FAs. Cytokines produced by FTC and FA were profiled using antibody array, and validated by quantitative PCR. Chemotaxis of monocyte THP-1 was induced by condition medium of FTC cell lines (FTC133 and WRO82-1) with and without anti-CCL15 neutralizing antibody. Finally, we analyzed CCL15 protein level in FTC and FA by immunohistochemistry.
RESULTS: The average density of CD68(+) cells was 9.5 ± 5.4/field in FTC, significantly higher than that in FA (4.9 ± 3.4/field, p < 0.001). Subsequently profiling showed that CCL15 was the most abundant chemokine in FTC compared with FA. CCL15 mRNA in FTC was 51.4-folds of that in FA. CM of FTC cell lines induced THP-1 cell chemotaxis by 33 ~ 77%, and anti-CCL15 neutralizing antibody reduced THP-1 cell migration in a dose-dependent manner. Moreover, we observed positive CCL15 immunostaining in 67.8% of FTCs compared with 23.4% of FAs.
CONCLUSION: Our study suggested FTC might induce TAMs infiltration by producing CCL15. Measurement of TAMs and CCL15 in follicular thyroid lesions may be applied clinically to differentiate FTC from FA pre-operation.

Henning JD, Bunker CH, Patrick AL, Jenkins FJ
Human herpesvirus 8 establishes a latent infection in prostates of Tobago men resulting in increased macrophage infiltration.
Prostate. 2016; 76(8):735-43 [PubMed] Related Publications
BACKGROUND: The Caribbean island of Tobago, which is 97% African ancestry, has one of the highest rates of prostate cancer in the world. We have previously reported that human herpesvirus 8 (HHV-8) infection is significantly associated with prostate cancer in Tobago. In this study, we extend those results testing the hypothesis that HHV-8 seropositive Tobagonian men have a chronic HHV-8 infection in their prostates that is associated with increased inflammation.
METHODS: Prostate sections were screened by immunohistochemistry for the expression of HHV-8 proteins K8.1 and LANA-1 and for presence of B cells (CD20) and macrophages (CD68).
RESULTS: HHV-8 antigen expression representing lytic and latent infections was seen in 73.9% of prostates from HHV-8 seropositive subjects. Latent infections were seen predominantly in glandular epithelia whereas lytic gene expression was seen mainly in macrophages in prostate stroma. Macrophage infiltrates were significantly increased in sections expressing HHV-8 proteins.
CONCLUSION: HHV-8 establishes a chronic latent infection in the prostate, which is associated with an increased macrophage infiltrate.

Hu Y, He MY, Zhu LF, et al.
Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma.
J Exp Clin Cancer Res. 2016; 35:12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Both tumor-associated macrophages (TAMs) and the epithelial to mesenchymal transition (EMT) of cancer cells play key roles in promoting tumor progression. However, whether TAMs could induce EMT in the progression of oral squamous cell carcinoma (OSCC) remains undefined.
RESULTS: Here we detected the expression of macrophages markers CD68 and CD163, epithelial marker E-cadherin and mesenchymal marker vimentin in 127 OSCC patients by using semi-quantitative immunohistochemistry. CD68 and CD163 expression was not confined to the infiltrating TAMs, but also detected in cancer cells. The high number of CD68-positive macrophages was correlated with poor overall survival. Meanwhile, the expression of CD163 both in macrophages and in cancer cells was associated with poor overall survival and had a significant prognostic impact in OSCC. Importantly, the expression of CD163 in cancer cells had a significant relationship with E-cadherin and vimentin. Furthermore, the incubation of TAMs conditioned medium resulted in a fibroblast-like appearance of cancer cells (HN4, HN6 and SCC9) together with the decreased/increased expression of E-cadherin/ vimentin, which were correlated with the enhanced ability of migration and invasion.
CONCLUSIONS: Our results indicate that TAMs could promote the EMT of cancer cells, thereby leading to the progression of oral cancer.

Ning C, Xie B, Zhang L, et al.
Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen.
Cancer Res. 2016; 76(6):1354-66 [PubMed] Related Publications
Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68(+)CD163(+) macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68(+)CD163(+) macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting.

Erreni M, Siddiqui I, Marelli G, et al.
The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination.
J Immunol. 2016; 196(2):902-14 [PubMed] Related Publications
Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancer-related death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential gene-profiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CL1 did not correlate with the density of tumor-infiltrating CD3(+) T cells or CD68(+) macrophages. Coexpression of ligand and receptor by tumor cells (axis-positive tumors) significantly associated with longer disease-free (p = 0.01) and disease-specific survival (p = 0.001). Conversely, axis-negative tumors (with low expression of both ligand and receptor) had increased risk of tumor relapse (p = 0.02), and increased likelihood of metachronous metastasis (p = 0.001), including after stage adjustment (p = 0.006). Transduction of CX3CL1 and CX3CR1 in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleen-liver metastases, cancer dissemination to liver was dramatically reduced in CX3CL1-CX3CR1-expressing tumors, and ligand-receptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX3CL1-CX3CR1 chemokine axis functions as a retention factor, increasing homotypic cell adhesion and limiting tumor spreading to metastatic sites. Lack or low levels of expression of CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.

Yamaguchi T, Fushida S, Yamamoto Y, et al.
Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination.
Gastric Cancer. 2016; 19(4):1052-65 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer.
METHODS: The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model.
RESULTS: The number of peritoneal macrophages with the M2 phenotype (CD68(+)CD163(+) or CD68(+)CD204(+)) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-α, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model.
CONCLUSIONS: Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer.

Qu QX, Huang Q, Shen Y, et al.
The increase of circulating PD-L1-expressing CD68(+) macrophage in ovarian cancer.
Tumour Biol. 2016; 37(4):5031-7 [PubMed] Related Publications
Tumor-associated macrophages (TAMs) have been characterized as a critical population of immunosuppressive cells in a variety of tumor types. PD-L1 (also termed B7-H1) has been described to exert co-inhibitory and immune regulatory functions. Here, in ovarian cancer, PD-L1 is selectively overexpressed on some TAM compared that of benign ovarian disease. When expanding the data in peripheral blood, the proportion of PD-L1(+)CD68(+) cell among CD68(+) cells and the intensity of PD-L1 staining on CD68(+) cell in healthy group were similar to that observed in ovarian cyst group; instead, these two measures were significantly higher in ovarian cancer group, thereafter related to TNM stage. Interestingly, intracellular levels of IL-10, IL-6, TNF-α, and IFN-γ in PD-L1(+)CD68(+) macrophage were higher than those in PD-L1(-)CD68(+) macrophage, especially IL-6 expression. Based on the PD-L1 receptor PD-1 expression on tumor-infiltrating cytotoxic cells, our data supported that expression of PD-L1 on TAM promoted apoptosis of T cells via interaction with PD-1 on CD8(+)T cells. Taken together, these results suggested that PD-L1-expressing macrophage represents a novel suppressor cell population in ovarian cancer, which contributes immune escape of ovarian cancer.

Zhuang PY, Wang JD, Tang ZH, et al.
Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma.
BMC Cancer. 2015; 15:830 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).
METHODS: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.
RESULTS: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.
CONCLUSIONS: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.

Giordano G, Febbraro A, Tomaselli E, et al.
Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer.
J Exp Clin Cancer Res. 2015; 34:108 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR "cetuximab" or VEGF "bevacizumab" in metastatic colorectal cancer (mCRC) patients.
METHODS: Infiltrating immune cells into tumor tissues, cancer-related expression of immune antigens (CD3, CD8, CD68, CD73, MPO, CD15/FUT4) from 102 mCRC patients receiving first-line Cetuximab or Bevacizumab plus chemotherapy were assessed by immunohistochemistry and validated in an independent tissue microarrays of 140 patients. Genome-wide expression profiles from 436 patients and 60 colon cancer cell lines were investigated using bioinformatics analysis. In vitro kinase assays of target genes activated by chemokines or growth factors were performed.
RESULTS: Here, we report that cancer-related CD15/FUT4 is overexpressed in most of mCRCs patients (43 %) and associates with lower intratumoral CD3+ and CD8+ T cells, higher systemic inflammation (NLR at diagnosis >5) and poorer outcomes, in terms of response and progression-free survival than those CD15/FUT4-low or negative ones (adjusted hazard ratio (HR) = 2.92; 95 % CI = 1.86-4.41; P < 0.001). Overexpression of CD15/FUT4 is induced through RAF-MEK-ERK kinase cascade, suppressed by MEK inhibitors and exhibits a close connection with constitutive oncogenic signalling pathways that respond to ERBB3 or FGFR4 activation (P < 0.001). CD15/FUT4-high expressing colon cancer cells with primary resistance to cetuximab or bevacizumab are significantly more sensitive to MEK inhibitors than CD15/FUT4-low counterparts.
CONCLUSION: Cancer-related CD15/FUT4 overexpression participates in cetuximab or bevacizumab mechanisms of resistance in mCRC patients. CD15/FUT4 as a potential target of the antitumor immune response requires further evaluation in clinical studies.

Kikuma T, Nakamachi Y, Noguchi Y, et al.
A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene.
Int J Hematol. 2015; 102(6):713-8 [PubMed] Related Publications
We report here the first case of NPM1/RARA-positive acute promyelocytic leukemia (APL) preceded by myeloid sarcoma (MS) in the vertebra. A 52-year-old man was diagnosed with MS, as the tumor cells were positive for myeloperoxidase and CD68 but negative for CD163. After treatment with steroids and radiation, the size of the tumor was markedly reduced and peripheral blood count was normal. Bone marrow examination showed 89.2% consisted of unclassified promyelocytes characterized by round nuclei and abundant small azurophilic granules but no Auer rods. The results of chromosome analysis showed 46,XY,t(5;17)(q35;q12). Reverse-transcription polymerase chain reaction amplified the NPM1/RARA fusion transcripts derived from a combination of NPM1 exon 4 and RARA exon 5, or of NPM1 exon 1 and RARA exon 5; the latter of these has not been reported previously. Electron microscopic examination of the promyelocyte nuclei showed they were oval with mild nuclear chromatin condensation and small- to medium-sized nucleoli. Hematological and molecular complete remission was attained after induction therapy including all-trans retinoic acid. As MS was also diagnosed in two of the seven other reported cases of APL with NPM1/RARA, MS may occur more frequently in APL with NPM1/RARA than APL with PML/RARA.

Bednarz-Knoll N, Nastały P, Żaczek A, et al.
Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression.
Oncotarget. 2015; 6(29):26789-803 [PubMed] Free Access to Full Article Related Publications
Interactions between cancer cells and microenvironment are emerging issue in tumor progression. Aldehyde dehydrogenase 1 (ALDH1) is a recognized cancer stem cell marker but little is known about its role in intratumoral stroma. Therefore, we focused on ALDH1 expression in tumor-associated stroma of breast carcinomas (BrCa). Stromal and tumoral ALDH1 expression was evaluated immunohistochemically in BrCa and their lymph node metastases (LNMs), and related to clinico-pathological characteristics, patients' outcome, presence of CD68, HLADR, retinoic acid (RA) in stroma, and selected proteins in tumor cells. ALDH1(+) stromal cells were detected in 53% of 374 BrCa and 61% of 102 LNMs. ALDH1(+) stroma in primary tumor correlated to longer disease-free (p = 0.030), metastasis-free (p = 0.024), and overall survival (p = 0.043) having an independent prognostic impact on DFS (multivariate analysis, p = 0.047). It was associated with concomitant presence of HLA-DR(+) stromal cells and RA in tumor cells (both p < 0.001), and inversely associated with vimentin expression in tumor cells (p = 0.036). ALDH1(+) stroma in LNMs correlated inversely to presence of disseminated tumor cells in patients' bone marrow (p = 0.014) and was independent prognosticator of shorter DFS and MFS (multivariate analysis, p = 0.004 and p = 0.002, respectively). In conclusion, ALDH1 expression in tumor-associated stromal cells indicates reduced BrCa progression, possibly via RA secretion.

Mori K, Haraguchi S, Hiori M, et al.
Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment.
BMC Cancer. 2015; 15:573 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor-associated macrophages (TAMs) are implicated in the growth, invasion and metastasis of various solid tumors. However, the phenotype of TAMs in premalignant lesions of solid tumors has not been clarified. In the present study, we identify the phenotype of TAMs in leukoplakia, an oral premalignant lesion, by immunohistochemical analysis and investigate the involvement of infiltrated T cells that participate in the polarization of TAMs.
METHODS: The subjects included 30 patients with oral leukoplakia and 10 individuals with normal mucosa. Hematoxylin and eosin slides were examined for the histological grades, and immunohistochemical analysis was carried out using antibodies against CD68 (pan-MΦ), CD80 (M1 MΦ), CD163 (M2 MΦ), CD4 (helper T cells: Th), CD8 (cytotoxic T cells), CXCR3, CCR5 (Th1), CCR4 (Th2), signal transducer and activator of transcription (STAT1), phosphorylated STAT1 (pSTAT1) and chemokine CXCL9. The differences in the numbers of positively stained cells among the different histological grades were tested for statistical significance using the Kruskal-Wallis test. Correlations between different types of immune cells were determined using Spearman's rank analysis.
RESULTS: An increase in the rate of CD163(+) TAM infiltration was observed in mild and moderate epithelial dysplasia, which positively correlated with the rate of intraepithelial CD4(+) Th cell infiltration. Although CCR4(+) cells rarely infiltrated, CXCR3(+) and CCR5(+) cells were observed in these lesions. Cells positive for STAT1 and chemokine CXCL9, interferon- (IFN)-induced gene products, and pSTAT1 were also observed in the same lesions. Double immunofluorescence staining demonstrated that the cells that were positive for CD163 were also positive for STAT1.
CONCLUSIONS: CD163(+) TAMs in oral premalignant lesions coexpress CD163 and STAT1, suggesting that the TAMs in oral premalignant lesions possess an M1 phenotype in a Th1-dominated micromilieu.

Tian Y, Wang J, Li M, et al.
Rosai-Dorfman disease involving the central nervous system: seven cases from one institute.
Acta Neurochir (Wien). 2015; 157(9):1565-71 [PubMed] Related Publications
BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, idiopathic, non-neoplastic histioproliferative disease. Central nervous system (CNS) manifestations are extremely rare. Its low incidence and unknown etiology restrict early diagnosis and optimal therapy.
METHODS: In the 1995-2013 period, seven CNS-RDD patients with intracranial and/or spinal lesions were retrospectively analyzed, including the clinical data, laboratory and imaging results, treatment applied and outcome. All seven case samples were screened for the SLC29A3 gene mutation, and the literature was reviewed.
RESULTS: Seven RDD patients (6 male/1 female, aged between 7 and 68) with CNS manifestations are reported. Five of the seven patients (71.4 %) had intracranial lesions (1 with skull erosion and 1 with multiple lesions mimicking meningiomas), and two (28.6 %) had spinal subdural lesions. The patients' symptoms included headaches, seizures, visual loss, epileptoid convulsions in the lower legs, fever, spastic paraparesis and paraplegia. An elevated erythrocyte sedimentation rate (ESR) was detected in five of the seven cases. The diagnosis was confirmed by immunohistochemical staining revealing that the characteristic histiocytes were positive for the S100 protein and CD68 and negative for CD1a. All patients were operated on: three recovered completely, two were partially rehabilitated, and two died. No SLC29A3 gene mutations were found in any of the seven samples.
CONCLUSION: This short series suggests the following: (1) RDD should be included in the differential diagnosis of lesions mimicking intracranial/spinal meningiomas or inflammatory lesions, especially in children; (2) the definitive diagnosis is based on histopathology and immunocytochemistry; (3) surgical resection seems to be the most effective therapy; (4) the exact etiology and adjuvant therapy for relapsing/incompletely resected lesions remain to be established.

Dang W, Tang H, Cao H, et al.
Strategy of STAT3β cell-specific expression in macrophages exhibits antitumor effects on mouse breast cancer.
Gene Ther. 2015; 22(12):977-83 [PubMed] Related Publications
Recent studies underscore the importance of crosstalk between tumor-associated macrophages (TAMs) and tumor cells in cancer progression and metastasis. In our study, AdCD68STAT3β, a recombinant adenovirus containing a STAT3β gene driven by CD68 macrophage-specific promoter, was used to suppress STAT3 and the downstream signaling pathways in TAMs. The results showed that STAT3β gene under the control of CD68 macrophage-specific promoter was only expressed in macrophages, which significantly inhibited the motility and invasion of breast cancer cells when co-cultured with 4T1 cells. Moreover, cell-specific STAT3β expression in TAMs extended survival of tumor-bearing mice and suppressed breast tumor growth, angiogenesis and metastasis, by regulating the crosstalk between tumor cells and TAMs. Therefore, our study provided a novel strategy for the antitumor effects of STAT3β.

Martín-Moreno AM, Roncador G, Maestre L, et al.
CSF1R Protein Expression in Reactive Lymphoid Tissues and Lymphoma: Its Relevance in Classical Hodgkin Lymphoma.
PLoS One. 2015; 10(6):e0125203 [PubMed] Free Access to Full Article Related Publications
Tumour-associated macrophages (TAMs) have been associated with survival in classic Hodgkin lymphoma (cHL) and other lymphoma types. The maturation and differentiation of tissue macrophages depends upon interactions between colony-stimulating factor 1 receptor (CSF1R) and its ligands. There remains, however, a lack of consistent information on CSF1R expression in TAMs. A new monoclonal antibody, FER216, was generated to investigate CSF1R protein distribution in formalin fixed tissue samples from 24 reactive lymphoid tissues and 187 different lymphoma types. We also analysed the distribution of CSF1R+, CD68+ and CD163+ macrophages by double immunostaining, and studied the relationship between CSF1R expression and survival in an independent series of 249 cHL patients. CSF1R+ TAMs were less frequent in B-cell lymphocytic leukaemia and lymphoblastic B-cell lymphoma than in diffuse large B-cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and cHL. HRS cells in cHL and, with the exception of three cases of anaplastic large cell lymphoma, the neoplastic cells in NHLs, lacked detectable CSF1R protein. A CSF1R+ enriched microenvironment in cHL was associated with shorter survival in an independent series of 249 cHL patients. CSF1R pathway activation was evident in the cHL and inactivation of this pathway could be a potential therapeutic target in cHL cases.

Choi J, Stradmann-Bellinghausen B, Yakubov E, et al.
Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages.
Cancer Biol Ther. 2015; 16(8):1205-13 [PubMed] Free Access to Full Article Related Publications
Glioblastoma cells produce and release high amounts of glutamate into the extracellular milieu and subsequently can trigger seizure in patients. Tumor-associated microglia/macrophages (TAMs), consisting of both parenchymal microglia and monocytes-derived macrophages (MDMs) recruited from the blood, are known to populate up to 1/3 of the glioblastoma tumor environment and exhibit an alternative, tumor-promoting and supporting phenotype. However, it is unknown how TAMs respond to the excess extracellular glutamate in the glioblastoma microenvironment. We investigated the expressions of genes related to glutamate transport and metabolism in human TAMs freshly isolated from glioblastoma resections. Quantitative real-time PCR analysis showed (i) significant increases in the expressions of GRIA2 (GluA2 or AMPA receptor 2), SLC1A2 (EAAT2), SLC1A3 (EAAT1), (ii) a near-significant decrease in the expression of SLC7A11 (cystine-glutamate antiporter xCT) and (iii) a remarkable increase in GLUL expression (glutamine synthetase) in these cells compared to adult primary human microglia. TAMs co-cultured with glioblastoma cells also exhibited a similar glutamatergic profile as freshly isolated TAMs except for a slight increase in SLC7A11 expression. We next analyzed these genes expressions in cultured human MDMs derived from peripheral blood monocytes for comparison. In contrast, MDMs co-cultured with glioblastoma cells compared to MDMs co-cultured with normal astrocytes exhibited decreased expressions in the tested genes except for GLUL. This is the first study to demonstrate transcriptional changes in glutamatergic signaling of TAMs in a glioblastoma microenvironment, and the findings here suggest that TAMs and MDMs might potentially elicit different cellular responses in the presence of excess extracellular glutamate.

Wincewicz A, Kowalik A, Zięba S, et al.
α-Fetoprotein-Producing Hepatoid Gastric Adenocarcinoma With Osteoclast-Like Giant Cells and Neuroendocrine Differentiation: A Case Study With Molecular Profiling.
Int J Surg Pathol. 2015; 23(7):537-41 [PubMed] Related Publications
Here we present the case of a 73-year-old woman with an ulcerated, advanced, hepatoid, and α-fetoprotein-producing poorly differentiated (G3) primary gastric adenocarcinoma pT3 N3a M1 with multinucleated cells and evident neuroendocrine component. This tumor was consistent with giant cell tumor type gastric carcinoma with osteoclast-like giant cells (OGCs). The cancer was HER2 and E-cadherin negative, chromogranin A dispersedly and moderately positive, and strongly α-fetoprotein-positive with evident CK AE1/AE3 immunoreactivity, while OGCs expressed CD68. To provide an insight into the molecular background of this peculiar neoplasm, next-generation sequencing (NGS) was performed to analyze the 50 most frequently mutated oncogenes and tumor suppressors. We detected mutations in the primary tumor in the following genes: KIT, EGFR, PTEN, ATM, and RB1. In the liver metastasis, we revealed mutations in 3 genes: PIK3CA, KIT, and CDKN2A.

Khoo BL, Lee SC, Kumar P, et al.
Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy.
Oncotarget. 2015; 6(17):15578-93 [PubMed] Free Access to Full Article Related Publications
Circulating tumor cells (CTCs) are considered as surrogate markers for prognosticating and evaluating patient treatment responses. Here, 226 blood samples from 92 patients with breast cancer, including patients with newly diagnosed or metastatic refractory cancer, and 16 blood samples from healthy subjects were cultured in laser-ablated microwells. Clusters containing an increasing number of cytokeratin-positive (CK+) cells appeared after 2 weeks, while most blood cells disappeared with time. Cultures were heterogeneous and exhibited two distinct sub-populations of cells: 'Small' (≤ 25 μm; high nuclear/cytoplasmic ratio; CD45-) cells, comprising CTCs, and 'Large' (> 25 μm; low nuclear/cytoplasmic ratio; CD68+ or CD56+) cells, corresponding to macrophage and natural killer-like cells. The Small cell fraction also showed copy number increases in six target genes (FGFR1, Myc, CCND1, HER2, TOP2A and ZNF217) associated with breast cancer. These expanded CTCs exhibited different proportions of epithelial-mesenchymal phenotypes and were transferable for further expansion as spheroids in serum-free suspension or 3D cultures. Cluster formation was affected by the presence and duration of systemic therapy, and its persistence may reflect therapeutic resistance. This novel and advanced method estimates CTC clonal heterogeneity and can predict, within a relatively short time frame, patient responses to therapy.

Wang B, Liu H, Dong X, et al.
High CD204+ tumor-infiltrating macrophage density predicts a poor prognosis in patients with urothelial cell carcinoma of the bladder.
Oncotarget. 2015; 6(24):20204-14 [PubMed] Free Access to Full Article Related Publications
Macrophages (Mφs) are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study attempted to investigate the prognostic values of various tumor-infiltrating Mφ phenotypes in patients with urothelial cell carcinoma of the bladder (UCB), with a focus on Mφ tissue microlocalization. Mφs were assessed by immunohistochemistry in tissues from 302 UCB patients using CD68 as a pan-Mφ marker, and CD204 and CD169 as robust pro- and anti-tumoral Mφ phenotype markers, respectively. Our data showed that these Mφ phenotypes were predominately distributed in stromal (ST) rather than in intratumoral (INT) regions (all P < 0.0001). Surprisingly, CD204 and CD169 can be co-expressed by the same CD68+ Mφs. Kaplan-Meier analysis revealed that all INT- and ST-infiltrating CD204+ or CD169+ Mφ densities were inversely associated with overall survival (all P < 0.01). By multivariate analysis, ST-infiltrating CD204+ Mφ density emerged as an independent prognostic factor for overall survival (HR, 1.981; P = 0.022). Moreover, the density of ST-infiltrating CD204+ Mφs was positively associated with the tumor size (P = 0.001), tumor stage (P < 0.0001), nodal metastasis (P < 0.0001), and histological grade (P < 0.0001). Our findings suggest that CD204+ Mφs might play detrimental protumoral roles and represent the predominant Mφ phenotype in human bladder cancer.

Barros MH, Segges P, Vera-Lozada G, et al.
Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival.
PLoS One. 2015; 10(5):e0124531 [PubMed] Free Access to Full Article Related Publications
Macrophages have been implicated in the pathogenesis of classical Hodgkin lymphoma (cHL) and have been suggested to have a negative impact on outcome. Most studies addressing the role of macrophages in cHL have relied on identification of macrophages by generic macrophage antigens, e.g., CD68. We have therefore conducted an in situ analysis of macrophage polarization in a series of 100 pediatric cHL (pcHL) cases using double staining immunohistochemistry, combining CD68 or CD163 with pSTAT1 (M1-like) or CMAF (M2-like). M1- or M2-polarised microenvironment was defined by an excess of one population over the other (>1.5). Expression of STAT1 and LYZ genes was also evaluated by RT-qPCR. Patients <14 years and EBV+ cases displayed higher numbers of CD68+pSTAT1+ cells than older children and EBV- cases, respectively (P=0.01 and P=0.02). A cytotoxic tumor microenvironment, defined by a CD8+/FOXP3+ ratio >1.5 was associated with higher numbers of CD68+pSTAT1+ (P=0.025) and CD163+pSTAT1+ macrophages (P<0.0005). Levels of STAT1 and LYZ expression were associated with the numbers of CD68+pSTAT1+ macrophages. EBV+ cHL cases disclosed a predominant M1 polarized microenvironment similar to Th1 mediated inflammatory disorders, while EBV- cHL showed a predominant M2 polarized microenvironment closer to Th2 mediated inflammatory diseases. Better overall-survival (OS) was observed in cases with higher numbers of CD163+pSTAT1+ macrophages (P=0.02) while larger numbers of CD163+CMAF+ macrophages were associated with worse progression-free survival (PFS) (P=0.02). Predominant M1-like polarization as disclosed by CD163+pSTAT1+/CD163+CMAF+ ratio > 1.5 was associated with better OS (P= 0.037). In conclusion, macrophage polarization in pcHL correlates with prevalent local T cell response and may be influenced by the EBV-status of neoplastic cells. Besides, M1-like and M2-like macrophages displayed differential effects on outcome in pcHL.

O'Shannessy DJ, Somers EB, Wang LC, et al.
Expression of folate receptors alpha and beta in normal and cancerous gynecologic tissues: correlation of expression of the beta isoform with macrophage markers.
J Ovarian Res. 2015; 8:29 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Folate receptor alpha (FOLR1/FRA) is expressed in a number of epithelial cancers and in particular epithelial ovarian cancer (EOC), especially of the serous histotype. Recent studies have shown that EOC originates from the fallopian tube fimbriae rather than from epithelial cells lining the ovary. We have previously shown by immunohistochemistry a strong correlation between FRA expression in EOC and normal and fallopian adenocarcinoma. Folate receptor beta (FOLR2/FRB) has been described to be expressed by macrophages both in inflammatory disorders and certain epithelial cancers. Given the high sequence identity of these two folate receptor family members we sought to investigate the architectural and cell-specific expression of these two receptors in gynecologic tissues.
METHODS: RNA scope, a novel chromogenic in situ hybridization assay tool, was used to examine expression of the alpha (FOLR1) and beta (FOLR2) isoforms of folate receptor relative to each other as well as to the macrophage markers CD11b and CD68, in samples of normal fallopian tube and fallopian adenocarcinoma as well as normal ovary and EOC.
RESULTS: We demonstrated expression of both FOLR1 and FOLR2 in EOC, normal fallopian tube and fallopian adenocarcinoma tissue while very little expression of either marker was observed in normal ovary. Furthermore, FOLR2 was shown to be expressed almost exclusively in macrophages, of both the M1 and M2 lineages, as determined by co-expression of CD11b and/or CD68, with little or no expression in epithelial cells.
CONCLUSIONS: These findings further substantiate the hypothesis that the cell of origin of EOC is tubal epithelium and that the beta isoform of folate receptor is primarily restricted to macrophages. Further, macrophages expressing FOLR2 may represent tumor associated or infiltrating macrophages (TAMs) in epithelial cancers.

Romano E, Kusio-Kobialka M, Foukas PG, et al.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Proc Natl Acad Sci U S A. 2015; 112(19):6140-5 [PubMed] Free Access to Full Article Related Publications
Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

Hira VV, Ploegmakers KJ, Grevers F, et al.
CD133+ and Nestin+ Glioma Stem-Like Cells Reside Around CD31+ Arterioles in Niches that Express SDF-1α, CXCR4, Osteopontin and Cathepsin K.
J Histochem Cytochem. 2015; 63(7):481-93 [PubMed] Related Publications
Poor survival of high-grade glioma is at least partly caused by glioma stem-like cells (GSLCs) that are resistant to therapy. GSLCs reside in niches in close vicinity of endothelium. The aim of the present study was to characterize proteins that may be functional in the GSLC niche by performing immunohistochemistry on serial cryostat sections of human high-grade glioma samples. We have found nine niches in five out of five high-grade glioma samples that were all surrounding arterioles with CD31+ endothelial cells and containing cellular structures that were CD133+ and nestin+. All nine niches expressed stromal-derived factor-1α (SDF-1α), its receptor C-X-C chemokine receptor type 4 (CXCR4), osteopontin and cathepsin K. SDF-1α plays a role in homing of CXCR4+ stem cells and leukocytes, whereas osteopontin and cathepsin K promote migration of cancer cells and leukocytes. Leukocyte-related markers, such as CD68, macrophage matrix metalloprotease-9, CD177 and neutrophil elastase were often but not always detected in the niches. We suggest that SDF-1α is involved in homing of CXCR4+ GSLCs and leukocytes and that cathepsin K and osteopontin are involved in the migration of GSLCs out of the niches.

Shi H, Li H, Zhen T, et al.
Clinicopathological features of angiomatoid fibrous histiocytoma: a series of 21 cases with variant morphology.
Int J Clin Exp Pathol. 2015; 8(1):772-8 [PubMed] Free Access to Full Article Related Publications
We analyzed the clinicopathological features of angiomatoid fibrous histiocytoma (AFH) in 21 cases with emphasis on variant morphology. In our series, ten patients were male and eleven were female. The patients' mean age was 26.9 years old. Tumors were located on the lower limbs in eight cases, upper limbs in three, trunk in five, head and neck in four, and trachea in one. Microscopically, thirteen cases were characterized by typical AFH. Tumor cells showed marked tumor pleomorphism with giant hyperchromatic nuclei in two cases. Mitotic figures (2-3/10HPF) were found in two cases. Focal necrosis was found in one case. A number of multinucleated giant cells were found in two cases. Two cases showed obvious myxoid change in the stromal. Prominent sclerosing changes in the stromal component were found in two cases. Immunohistochemistry staining showed tumor cells were positive for EMA, desmin, and CD68. Five cases demonstrated the presence of rearrangement of the EWSR1 gene by FISH detection. Only two patients had tumor recurrence at 3 and 6 months after tumor resection, respectively. In conclusion, AFH has variant histological patterns. The differential diagnosis includes inflammatory myofibroblastic tumor, aneurysmal fibrous histiocytoma, follicular dendritic cell tumor, and metastatic tumor of lymph node.

Armaiz-Pena GN, Gonzalez-Villasana V, Nagaraja AS, et al.
Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth.
Oncotarget. 2015; 6(6):4266-73 [PubMed] Free Access to Full Article Related Publications
Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production.

Hu ZL, Sang H, Deng L, Li Z
Subcutaneous Panniculitis-Like T-Cell Lymphoma in Children: A Review of the Literature.
Pediatr Dermatol. 2015 Jul-Aug; 32(4):526-32 [PubMed] Related Publications
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a type of skin lymphoma. Pleomorphic T-cells infiltrate the subcutaneous tissue and mimic lobular panniculitis. We report a case occurring in a 12-year-old Chinese boy who presented with multiple indolent erythematous subcutaneous nodules on both extremities without systemic symptoms. He had a protracted course of multiple erythematous subcutaneous nodules for 1 year and underwent biopsy of lesional skin for histology and T-cell receptor (TCR) gene analysis. Histopathology showed infiltration of medium to large atypical pleomorphic cells involving the subcutis with characteristic rimming of fat spaces. TCR gene rearrangement shows monoclonal rearrangements of the TCR β and γ chains. Immunophenotypic studies showed that CD3, CD4, and CD8 were strongly and diffusely positive in lesional cells and that CD56 was focally positive. In contrast, these cells were negative for CD20, CD30, and CD68. The combined morphology, characteristic histologic features, and positive T-CR gene rearrangement supported a diagnosis of SPTCL. He is being treated with combination chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Scott DW, Steidl C
The classical Hodgkin lymphoma tumor microenvironment: macrophages and gene expression-based modeling.
Hematology Am Soc Hematol Educ Program. 2014; 2014(1):144-50 [PubMed] Related Publications
Despite the high cure rate in classical Hodgkin lymphoma (CHL), more accurate tailoring of upfront treatment is required to maximize cure while avoiding unnecessary short- and long-term treatment side effects. To this end, the unique tumor microenvironment of CHL has been searched extensively for prognostic biomarkers. Beyond targeted immunohistochemistry (IHC) studies, gene expression profiling (GEP) of diagnostic whole tissue biopsies has allowed a de novo approach to biomarker discovery. Among numerous candidate biomarkers, an association between the number of tumor-associated macrophages in the microenvironment and outcomes after ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) chemotherapy emerged, and multiple subsequent studies have validated this biological relationship using IHC. These studies have also defined key aspects for macrophage interrogation, including the characteristics of the CD68 and CD163 antibodies, appropriate scoring methodologies, and the identification of specific patient populations in which macrophage IHC may not be prognostic. The GEP studies also led to the development of gene expression-based prognostic models for advanced-stage CHL, with new technologies allowing reliable gene expression quantitation using RNA from routinely produced formalin-fixed paraffin-embedded biopsies. The bridge to predictive biomarkers that can be used reliably to inform upfront treatment selection requires further studies to demonstrate that these biomarkers can identify robustly, at diagnosis, patients at high risk of treatment failure with ABVD and that this risk may be overcome using alternative treatments.

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