Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

Sunami, Yoshiaki; Häußler, Johanna; Zourelidis, Anais; Kleeff, Jörg

doi:10.3390/cancers14030744

Cited by 17 publications

(18 citation statements)

References 77 publications

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“…Microsatellite instability-high (MSI-H) and/or defect mismatch repair (dMMR) gene incidence in pancreatic cancer is less than 1%, which precludes the potential application of PD-1 blockade in pancreatic cancer ( 22 , 23 ). Furthermore, pancreatic cancer has a denser stroma and a more complex tumor immune microenvironment compared with other solid tumors ( 24 ). For the purpose of improving the treatment effect of PD-1 inhibitors, researchers have tried a variety of methods and found that radiotherapy could modulate the tumor environment, thereby improving the antitumor response.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Pathologic Complete Response to Induction Therapy in a Patient With Potentially Resectable Pancreatic Cancer

Zhu²,

Cheng³

et al. 2022

Front. Oncol.

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Immune monotherapy does not appear to work in patients with pancreatic cancer so far. We are conducting a clinical trial that combines programmed cell death protein-1 (PD-1) inhibitor with chemotherapy and concurrent radiotherapy as induction therapy for patients with locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). Here, we report a case with a pathologic complete response (pCR) and no postoperative complications after the induction therapy. The patient received four cycles of induction therapy and achieved a partial response (PR) with a significant decline of tumor marker carbohydrate antigen 19-9 (CA19-9). Also, peripheral blood samples were collected during the treatment to investigate serial circulating tumor DNA (ctDNA) dynamic changes in predicting the tumor response and outcomes in patients. Our result suggested that PD-1 blockade plus chemotherapy and concurrent radiotherapy is a promising mode as induction therapy for patients with potentially resectable pancreatic cancer. In this case, serial ctDNA alterations accurately provide a comprehensive outlook of the tumor status and monitor the response to the therapy, as validated by standard imaging.

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Section: Discussionmentioning

confidence: 99%

Case Report: Pathologic Complete Response to Induction Therapy in a Patient With Potentially Resectable Pancreatic Cancer

Zhu²,

Cheng³

et al. 2022

Front. Oncol.

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“…CAFs play a significant role in the solid tumor microenvironment, including carcinomas of the intestine, breast, lung, and pancreas (40)(41)(42). The presence of CAFs in TMEs is linked to a poor prognosis and treatment resistance, angiogenesis and metastasis, disease recurrence, immunosuppression, ECM remodeling, and metabolic reprogramming (43,44).…”

Section: Cancer-associated Fibroblast As a Versatile Player In Tmementioning

confidence: 99%

Immune checkpoint inhibitors as mediators for immunosuppression by cancer-associated fibroblasts: A comprehensive review

Eskandari-Malayeri

Rezaei

2022

Front. Immunol.

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The tumor microenvironment (TME) is a significant contributor to cancer progression containing complex connections between cellular and chemical components and provides a suitable substrate for tumor growth and development. Growing evidence shows targeting tumor cells while ignoring the surrounding TME is not effective enough to overcome the cancer disease. Fibroblasts are essential sentinels of the stroma that due to certain conditions in TME, such as oxidative stress and local hypoxia, become activated, and play the prominent role in the physical support of tumor cells and the enhancement of tumorigenesis. Activated fibroblasts in TME, defined as cancer-associated fibroblasts (CAFs), play a crucial role in regulating the biological behavior of tumors, such as tumor metastasis and drug resistance. CAFs are highly heterogeneous populations that have different origins and, in addition to their role in supporting stromal cells, have multiple immunosuppressive functions via a membrane and secretory patterns. The secretion of different cytokines/chemokines, interactions that mediate the recruitment of regulatory immune cells and the reprogramming of an immunosuppressive function in immature myeloid cells are just a few examples of how CAFs contribute to the immune escape of tumors through various direct and indirect mechanisms on specific immune cell populations. Moreover, CAFs directly abolish the role of cytotoxic lymphocytes. The activation and overexpression of inhibitory immune checkpoints (iICPs) or their ligands in TME compartments are one of the main regulatory mechanisms that inactivate tumor-infiltrating lymphocytes in cancer lesions. CAFs are also essential players in the induction or expression of iICPs and the suppression of immune response in TME. Based on available studies, CAF subsets could modulate immune cell function in TME through iICPs in two ways; direct expression of iICPs by activated CAFs and indirect induction by production soluble and then upregulation of iICPs in TME. With a focus on CAFs’ direct and indirect roles in the induction of iICPs in TME as well as their use in immunotherapy and diagnostics, we present the evolving understanding of the immunosuppressive mechanism of CAFs in TME in this review. Understanding the complete picture of CAFs will help develop new strategies to improve precision cancer therapy.

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“…EV-mediated intracellular communication plays a role not only in maintaining cell homeostasis, but also in disease progression [ 96 , 97 , 98 , 99 ]. Exosomes are associated with several diseases, including cancer metastasis, which is the invasion and spread of primary cancer cells into other organs [ 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ]. Exosomes have been shown to play an important role in the formation of the cancer microenvironment and the mechanisms of cancer malignancy, such as cancer cell growth, infiltration, metastasis, and pre-metastasis niche [ 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ].…”

Section: Evs In Cancer Metastasis and Malignant Transformationmentioning

confidence: 99%

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

Matsuzaka

Yashiro

2022

IJMS

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Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by delivering their contents, such as nucleic acids, proteins, and lipids, to distant target cells. EVs play a role in the progression of several diseases. In particular, programmed death-ligand 1 (PD-L1) levels in exosomes are associated with cancer progression. Furthermore, exosomes are being used for new drug-delivery systems by modifying their membrane peptides to promote their intracellular transduction via micropinocytosis. In this review, we aim to show that an efficient drug-delivery system and a useful therapeutic strategy can be established by controlling the molecular docking and intracellular translocation of exosomes. We summarise the mechanisms of molecular docking of exosomes, the biological effects of exosomes transmitted into target cells, and the current state of exosomes as drug delivery systems.

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Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

Cited by 17 publications

References 77 publications

Case Report: Pathologic Complete Response to Induction Therapy in a Patient With Potentially Resectable Pancreatic Cancer

Case Report: Pathologic Complete Response to Induction Therapy in a Patient With Potentially Resectable Pancreatic Cancer

Immune checkpoint inhibitors as mediators for immunosuppression by cancer-associated fibroblasts: A comprehensive review

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

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