Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma

Kimbara, Shiro; Kondo, Shunsuke

doi:10.3748/wjg.v22.i33.7440

Cited by 16 publications

(11 citation statements)

References 96 publications

(106 reference statements)

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“…Metabolic reprogramming occurs in tumor cells to foster their rapid proliferation, their survival, and the formation of metastasis [ 207 ]. This reprogramming also supports the inflammation observed in neoplastic pathologies [ 208 , 209 ]. Fatty acid synthase (FASN, also known as onco-antigen 519), a key lipogenic enzyme involved in de novo lipid biosynthesis, is significantly upregulated in pancreatic tumor cells, which results in a significantly poor prognosis of patients [ 210 ].…”

Section: Introductionsupporting

confidence: 79%

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Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

et al. 2017

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Pancreatic adenocarcinomas and diabetes mellitus are responsible for the deaths of around two million people each year worldwide. Patients with chronic pancreatitis do not die directly of this disease, except where the pathology is hereditary. Much current literature supports the involvement of bile salt-dependent lipase (BSDL), also known as carboxyl ester lipase (CEL), in the pathophysiology of these pancreatic diseases. The purpose of this review is to shed light on connections between chronic pancreatitis, diabetes, and pancreatic adenocarcinomas by gaining an insight into BSDL and its variants. This enzyme is normally secreted by the exocrine pancreas, and is diverted within the intestinal lumen to participate in the hydrolysis of dietary lipids. However, BSDL is also expressed by other cells and tissues, where it participates in lipid homeostasis. Variants of BSDL resulting from germline and/or somatic mutations (nucleotide insertion/deletion or nonallelic homologous recombination) are expressed in the pancreas of patients with pancreatic pathologies such as chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We discuss the possible link between the expression of BSDL variants and these dramatic pancreatic pathologies, putting forward the suggestion that BSDL and its variants are implicated in the cell lipid metabolism/reprogramming that leads to the dyslipidemia observed in chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We also propose potential strategies for translation to therapeutic applications.

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Section: Introductionsupporting

confidence: 79%

“…Fatty pancreatic infiltration is a risk factor for early lesions in pancreatic cancer [ 206 ], and lipid metabolism is dysregulated in PAC [ 209 – 211 ]. Metabolic reprogramming occurs in tumor cells to foster their rapid proliferation, their survival, and the formation of metastasis [ 207 ].…”

Section: Introductionmentioning

confidence: 99%

Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

et al. 2017

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“…With inhibitors of such immune checkpoints receiving much attention in recent years due to their ability to break the cycle of immune suppression and thereby enable immune cell killing of the cancer cells [ 3 , 4 ], there is heightened interest in examining additional mechanisms used by cancer cells to suppress and shape immune responses. One particular area of interest in regard to new immunotherapeutic potentials would be to target inflammation and, in particular, the immune cells responsible for inflammation, especially in certain forms of cancer where standard immune checkpoint inhibitors have minimal benefit [ 5 ].…”

Section: A Growing Link Between Hypersialylation Cancer and Inflmentioning

confidence: 99%

Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Rodrigues

Macauley

2018

Cancers

175

173

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Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered glycosylation on cancers cells is gaining attention due its wide-spread occurrence across a variety of cancer types and recent studies that have documented functional roles for aberrant glycosylation in driving cancer progression at various stages. One change in glycosylation that can correlate with cancer stage and disease prognosis is hypersialylation. Increased levels of sialic acid are pervasive in cancer and a growing body of evidence demonstrates how hypersialylation is advantageous to cancer cells, particularly from the perspective of modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs and Selectins, are well-positioned to be exploited by cancer hypersialylation. Evidence is also mounting that Siglecs modulate key immune cell types in the tumor microenvironment, particularly those responsible for maintaining the appropriate inflammatory environment. From these studies have come new and innovative ways to block the effects of hypersialylation by directly reducing sialic acid on cancer cells or blocking interactions between sialic acid and Siglecs or Selectins. Here we review recent works examining how cancer cells become hypersialylated, how hypersialylation benefits cancer cells and tumors, and proposed therapies to abrogate hypersialylation of cancer.

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“…Finally, pancreatic cancer cells express cytotoxic-T-lymphocyte associated protein 4 (CTLA-4) and the ligand for programmed cell death protein-1 (PD-1), PD-L1 [ 32 ], which is activated by the EGFR/MAPK pathway from myeloid cells [ 33 ], inhibiting T cell function. Currently, CTLA-4 and PD-1/PD-L1 have been established as therapeutic targets [ 34 , 35 ]. These molecules can be blocked by monoclonal antibodies, including ipilimumab, nivolumab, and pembrolizumab.…”

Section: Introductionmentioning

confidence: 99%

Tumor microenvironment participates in metastasis of pancreatic cancer

et al. 2018

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Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial-mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival.

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Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma

Cited by 16 publications

References 96 publications

Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Tumor microenvironment participates in metastasis of pancreatic cancer

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