Tumor-Infiltrating Mast Cells in Colorectal Cancer as a Poor Prognostic Factor

Wu, Xianrui; Zou, Yifeng; He, Xiaosheng; Yuan, Ruixue; Chen, Yufeng; Lan, Nan; Lian, Lei; Wang, Fengwei; Fan, Xinjuan; Zeng, Yang; Ke, Jia; Wu, Xiaojian; Lan, Ping

doi:10.1177/1066896912448836

Cited by 24 publications

(22 citation statements)

References 42 publications

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“…17, 25 Of interest, a lower juxtatumoral T reg (FoxP3 + ) infiltrate also demonstrated a pro-survival effect in PDAC patients. Taken together, this data suggests that reduced infiltration of anti-tumor CD8 + T-cells to target tumor epithelial cells in the PDAC microenvironment has important clinical impact.…”

Section: Resultsmentioning

confidence: 99%

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

et al. 2013

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Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. Method We used tissue microarray analysis to compare immune cell infiltration of different pancreatico-biliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis), and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice, and the effects of all-trans retinoic acid (ATRA) on these processes. Results Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase+ and CD68+ cells, compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8+, FoxP3+, CD56+, or CD20+ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8+ T-cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8+ T-cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8+ T-cells from PDAC patients had increased chemotaxis towards activated PSCs, which secrete CXCL12, compared with quiescent PSC or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Conclusion Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8+ T-cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective anti-tumor immune response.

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Section: Resultsmentioning

confidence: 99%

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

et al. 2013

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“…Literature searches yield 11,417 records and the results were shown in Figure S1. Twenty eight studies containing 4,224 patients with solid tumor were identified for the assessment of tumor‐infiltrating tryptase + mast cells . All the studies were evaluated by the Newcastle–Ottawa Scale (NOS), and were in accordance with the inclusion criteria and suitable for data consolidation.…”

Section: Resultsmentioning

confidence: 99%

Tumor‐infiltrating tryptase⁺ mast cells predict unfavorable clinical outcome in solid tumors

Wang

Cheng

2017

Intl Journal of Cancer

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The prognostic role of tumor-infiltrating tryptase mast cells in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 28 published studies with 4224 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating tryptase mast cells in human solid tumors. We found that tryptase mast cell infiltration significantly decreased overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, tryptase mast cell infiltration was significantly associated with worse OS in non-small cell lung cancer, hepatocellular carcinoma and 5-year survival in colorectal cancer. And these cells were inversely associated with DFS in hepatocellular and colorectal cancer. In addition, high density of intratumoral tryptase mast cells significantly correlated with lymph node metastasis of solid tumor. In conclusion, Tryptase mast cell infiltration leads to an unfavorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances and targeting it may have a potential for effective treatment.

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“…Interestingly, we also demonstrated a significant MC increase in male patients compared with female patients in agreement with Wu et al . . This strong association seems to be related to the oestrogen/oestrogen receptor/tumour necrosis factor‐α axis; in fact, MCs express oestrogen receptors and treatment with the specific ligand has been demonstrated to prevent the release of TNF‐alpha, a major MC‐derived autocrine growth factor .…”

Section: Discussionmentioning

confidence: 99%

High density of tryptase‐positive mast cells in human colorectal cancer: a poor prognostic factor related to protease‐activated receptor 2 expression

Malfettone

Silvestris

Saponaro

et al. 2013

J Cellular Molecular Medi

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Tryptase(+) mast cells (MCs), abundant in the invasive front of tumours, contribute to tissue remodelling. Indeed, protease-activated receptor-2 (PAR-2) activation by MC-tryptase is considered an oncogenic event in colorectal cancer (CRC). Recently, we have suggested NHERF1 as a potential new marker in CRC. In this study, we aimed to determine the distribution of tryptase(+) MCs and PAR-2 and to examine the relationship between PAR-2 and NHERF1, investigating their reputed usefulness as tumour markers. We studied a cohort of 115 CRC specimens including primary cancer (C) and adjacent normal mucosa (NM) by immunohistochemical double staining, analyzing the protein expression of MC-tryptase, PAR-2 and cytoplasmic NHERF1. MC density was higher in NM than in C. Tumours with high TNM stage and poor grade showed the highest MC density. A higher PAR-2 immunoreactivity characterized tumours most infiltrated by MCs compared with samples with low MC density. Furthermore, PAR-2 overexpression was associated with advanced TNM stage, poor grade and lymphovascular invasion (LVI). A positive correlation existed between tryptase(+) MC density and PAR-2 expression. Cytoplasmic NHERF1 was higher in C than in NM and overexpressing tumours resulted associated with nodal and distant metastases, poor grade and LVI. PAR-2 correlated with cytoplasmic NHERF1 and the PAR-2(+)/cytoplasmic NHERF1(+) expression immunophenotype identified tumours associated with unfavourable prognosis and aggressive clinical parameters. Our data indicate that the high density of tryptase(+) MCs at invasive margins of tumours was associated with advanced stages of CRC and was strongly correlated with PAR-2 expression.

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Tumor-Infiltrating Mast Cells in Colorectal Cancer as a Poor Prognostic Factor

Cited by 24 publications

References 42 publications

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

Tumor‐infiltrating tryptase⁺ mast cells predict unfavorable clinical outcome in solid tumors

High density of tryptase‐positive mast cells in human colorectal cancer: a poor prognostic factor related to protease‐activated receptor 2 expression

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Tumor-Infiltrating Mast Cells in Colorectal Cancer as a Poor Prognostic Factor

Cited by 24 publications

References 42 publications

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

Tumor‐infiltrating tryptase+ mast cells predict unfavorable clinical outcome in solid tumors

High density of tryptase‐positive mast cells in human colorectal cancer: a poor prognostic factor related to protease‐activated receptor 2 expression

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Tumor‐infiltrating tryptase⁺ mast cells predict unfavorable clinical outcome in solid tumors