Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer

Bulle, Ashenafi Shiferaw; Dekervel, Jeroen; Deschuttere, Lise; Nittner, David; Libbrecht, Louis; Janky, Rekin’s; Plaisance, Stéphane; Topal, Baki; Coosemans, An; Lambrechts, Diether; Cutsem, Éric Van; Verslype, Chris; Pelt, Jos van

doi:10.1016/j.tranon.2020.01.004

Cited by 39 publications

(35 citation statements)

References 63 publications

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“…In addition, gemcitabine treatment results in robust infiltration of M2-polarized TAMs which secrete TNFα, TGF-β, and IL-6, leading to EMT of PDAC cells. 160 Therefore, tumor infiltrative M2 TAMs are another major propeller of PDAC EMT via providing various cytokines and chemokines.…”

Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning

confidence: 99%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

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114

135

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Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

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Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning

confidence: 99%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

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114

135

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“…In vitro experiments demonstrated that GEM-treated macrophages become tumoricidal, and postsurgical adjuvant GEM therapy in pancreatic ductal adenocarcinoma (PDAC) reprograms TAMs towards an M1-phenotype [ 98 ]. On the contrary, others have demonstrated that GEM promotes M2-polarization in pancreatic tumors [ 114 , 115 ].…”

Section: Chemotherapy Radiotherapy and Oncolytic Virus Inducingmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Belgiovine

Digifico

Anfray

et al. 2020

JCM

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In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

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“…In addition, we tested ACF in two human PDAC xenografts (PDTX): classical type (moderately differentiated and relative slow progression: PAC006) and quasi-mesenchymal type (poorly differentiated, EMT characteristics and faster growth: PAC010). 21,22 Importantly, in PDTX models the human stroma is replaced by murine stroma and we use this to dissect the molecular characteristics of the stroma (mouse) and tumor cells (human). 22 Further, in PDTX models, we can only investigate the tumor-infiltrating cells from the innate immune system of which a large fraction are the tumor-associated macrophages (TAMs).…”

Section: Introductionmentioning

confidence: 99%

“…21,22 Importantly, in PDTX models the human stroma is replaced by murine stroma and we use this to dissect the molecular characteristics of the stroma (mouse) and tumor cells (human). 22 Further, in PDTX models, we can only investigate the tumor-infiltrating cells from the innate immune system of which a large fraction are the tumor-associated macrophages (TAMs). Conventionally, these TAMs are classified as classical activated (M1, proinflammatory and anti-tumoral function) and nonclassical activated (M2, anti-inflammatory/protumoral) that reflect their distinct cellular function and metabolism.…”

Section: Introductionmentioning

confidence: 99%

<p>Anti-Cancer Activity of Acriflavine as Metabolic Inhibitor of OXPHOS in Pancreas Cancer Xenografts</p>

Bulle

Dekervel

Deschuttere

et al. 2020

OTT

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Purpose: All currently available therapies for the treatment of pancreatic ductal adenocarcinoma (PDAC) show limited success. PDACs fast progression depends on the tumor characteristics and can be influenced by the microenvironment. The antibacterial drug acriflavine (ACF) has been shown to have anti-cancer activities in cell lines. Materials and Methods: To understand the working mechanism of ACF on cancer progression and tumor-stromal interplay, we evaluated pancreatic cancer in cell culture (Panc-1) (morphology, cell invasion and RNA expression) and the macrophage cell line THP1 (representing innate immune stromal cells). In the translational arm, the activity of ACF on xenograft models of human PDAC tumors representing different clinical subclasses was investigated (tumor growth, morphology and immunofluorescence, RNA expression and pathway analysis). Results: In vitro, ACF reduces epithelial-to-mesenchymal transition (EMT) and invasion of Panc-1 cells and shifts macrophage polarization to a M1-like anti-tumoral phenotype. At non-toxic concentrations, ACF downregulates cell metabolism. In xenografts, effect on tumor growth and metabolism could be confirmed; however, the innate immune stromal cells did not respond. Importantly, only in the moderately differentiated PDAC model, ACF could significantly suppress tumor growth and not in the fast-growing EMT-high model. Pathway analysis shows that ACF highly significantly downregulates metabolic pathways, especially OXPHOS and MYC/cell proliferation pathways in xenografts. Conclusion: ACF, with known pleiotropic effects on cancer cells, is in this study shown to be an attractive therapeutic based on its novel observed metabolic activity. Repurposing this compound for cancer treatment should be in the setting with other targeting agents, which offers reduced chance of resistance development in PDAC. Further evaluation should best be done in biological complex models such as human xenografts or syngeneic cancer models.

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Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer

Cited by 39 publications

References 63 publications

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

<p>Anti-Cancer Activity of Acriflavine as Metabolic Inhibitor of OXPHOS in Pancreas Cancer Xenografts</p>

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