Tumor-Associated Macrophages Are a Useful Biomarker to Predict Recurrence After Surgical Resection of Nonfunctional Pancreatic Neuroendocrine Tumors

Wei, Iris; Harmon, Charles M.; Arcerito, Massimo; Cheng, David K.; Minter, Rebecca M.; Simeone, Diane M.

doi:10.1097/sla.0000000000000262

Cited by 52 publications

(52 citation statements)

References 51 publications

(51 reference statements)

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“…In analogy to our findings, Wei et al in 2014 reported a positive association between TAM infiltration and recurrence in a small cohort of 38 patients after curative resection of NF-PNETs. 24 In this report, TAM infiltration was only compared semiquantitatively. In contrast, in our series comprising >100 human samples, TAM infiltration was quantified in absolute numbers per HPF which to our knowledge represents the largest study on TAMs in human PNET tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In analogy to our findings, Wei et al . in 2014 reported a positive association between TAM infiltration and recurrence in a small cohort of 38 patients after curative resection of NF‐PNETs . In this report, TAM infiltration was only compared semiquantitatively.…”

Section: Discussionmentioning

confidence: 99%

“…The influence of infiltrating immune cells in neuroendocrine tumors has not been completely elucidated yet. In humans, infiltration of TAMs in primary PNETs correlates with proliferative activity, presence of liver metastases and disease recurrence after curative surgery . Preclinical studies to decipher the role of immune cells were performed using the RIP1Tag2 genetically engineered mouse model for pancreatic neuroendocrine tumors.…”

mentioning

confidence: 86%

“…In humans, infiltration of TAMs in primary PNETs correlates with proliferative activity, presence of liver metastases and disease recurrence after curative surgery. 23,24 Preclinical studies to decipher the role of immune cells were performed using the RIP1Tag2 genetically engineered mouse model for pancreatic neuroendocrine tumors. This model faithfully recapitulates the multistep process of insulinoma transformation, including the stages of hyperplastic islets, angiogenic islets and invasive tumors with various gradings.…”

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confidence: 99%

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Therapeutic targeting of tumor‐associated macrophages in pancreatic neuroendocrine tumors

Krug

Abbassi

Griesmann

et al. 2018

Intl Journal of Cancer

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Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behaviour and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage and grading. The effect of liposomal clodronate on TAM cell viability was analysed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human insulinomas TAM density was correlated with invasiveness and malignant behaviour. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80 positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET in particular in insulinomas and correlate with metastatic behaviour. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET. This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 86%

mentioning

confidence: 99%

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Therapeutic targeting of tumor‐associated macrophages in pancreatic neuroendocrine tumors

Krug

Abbassi

Griesmann

et al. 2018

Intl Journal of Cancer

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“…3 However, the recurrence rate is reported to be 13.5%-30%, [4][5][6][7] with the median duration from resection to recurrence from 2 to 3.3 years. 8 Certain studies identified mitotic rates, 2 nonfunctioning status, 2,4 tumor size > 2 cm, 9 G2 tumor grade, 4 N1 status, 9 and the presence of vascular invasion 4 as recurrence predictors. Studies have established a risk stratification to predict recurrence by combining TNM stage, Ki-67, 10 and functionality.…”

Section: Introductionmentioning

confidence: 99%

CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors

et al. 2019

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Although the postoperative recurrence rate for pancreatic neuroendocrine tumors (PNETs) is reported to be 13.5%‐30%, the paucity of valuable biomarkers to predict recurrence poses a problem for the early detection of relapse. Hence, this study aimed to identify new biomarkers to predict the recurrence of PNETs. We performed RNA sequencing (RNA‐Seq) on RNA isolated from frozen primary tumors sampled from all localized G1/G2 PNETs resected curatively from 1998 to 2015 in our institution. We calculated differentially expressed genes (DEGs) in tumor with and without recurrence (≥3 years) for the propensity‐matched cohort. Gene ontology analysis for the identified DEGs was also performed. Furthermore, we evaluated the expression levels of candidate genes as recurrence predictors via immunostaining. Comparison of transcriptional levels in tumors with and without recurrence identified 166 DEGs. Up‐ and downregulated genes with high significance in these tumors were mainly related to extracellular organization and cell adhesion, respectively. We observed the top three upregulated genes, C‐type lectin domain family 3 member A (CLEC3A), matrix metalloproteinase‐7 (MMP7), and lipocalin2 (LCN2) immunohistochemically and compared their levels in recurrent and nonrecurrent tumors. Significantly higher recurrence rate was shown in patients with positive expression of CLEC3A ( P = 0.028), MMP7 ( P = 0.003), and LCN2 ( P = 0.040) than that with negative expression. We identified CLEC3A, MMP7, and LCN2 known to be associated with the phosphatidylinositol‐3‐kinase/Akt pathway, as potential novel markers to predict the postoperative recurrence of PNETs.

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Protective Association Between Calcium Channel Blocker Use and Breast Cancer Recurrence in Postsurgical Women: A Population‐Based Case‐Control Study in Taiwan

Shih

Chung

Liao

et al. 2020

The Journal of Clinical Pharma

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Neoadjuvant chemotherapy induces metastasis of residual breast cancers through activation of tumor-associated macrophages. Previous studies have indicated that calcium channel blockers (CCBs) exert anti-inflammatory and antimigratory effects on macrophages via attenuating Ca 2+ entry into macrophages. However, no existing empirical research has addressed the relationship between previous CCB use and breast cancer recurrence. In this study, 4840 Taiwanese women aged ࣙ20 years with breast cancer who underwent breast surgery from January 1, 2007, to December 31, 2015, were enrolled. The date of cancer recurrence was defined as the index date. Logistic regression was performed to evaluate the relationship between previous CCB exposure and cancer recurrence among female patients who underwent surgery for breast cancer. After adjusting for demographic characteristics, comorbidities, and tumor-node-metastasis stage, the adjusted odds ratio (OR) for CCB exposure within 5 years before the index date in women with recurrence compared with nonrecurrent controls was 0.73 (95% confidence interval [CI], 0.53-0.97). Further analysis revealed that the adjusted OR for CCB exposure between the surgery and index dates in women with recurrence relative to nonrecurrent controls was 0.72 (95%CI, 0.66-0.95). In particular, prior CCB use was significantly associated with a lower risk (34%) of breast cancer recurrence among women 20 to 54 years old (OR, 0.66; 95%CI, 0.47-0.83). This study uncovered a protective association between previous CCB use and breast cancer recurrence.

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Tumor-Associated Macrophages Are a Useful Biomarker to Predict Recurrence After Surgical Resection of Nonfunctional Pancreatic Neuroendocrine Tumors

Cited by 52 publications

References 51 publications

Therapeutic targeting of tumor‐associated macrophages in pancreatic neuroendocrine tumors

Therapeutic targeting of tumor‐associated macrophages in pancreatic neuroendocrine tumors

CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors

Protective Association Between Calcium Channel Blocker Use and Breast Cancer Recurrence in Postsurgical Women: A Population‐Based Case‐Control Study in Taiwan

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