CAF-Derived IL6 and GM-CSF Cooperate to Induce M2-like TAMs–Letter

Iorio, Vittoria; Marco, Margot De; Basile, Anna; Eletto, Daniela; Coccia, Mario; Sala, Gianluca; Marzullo, Liberato; Turco, Maria Caterina; Laurenzi, Vincenzo De; Turco, Maria Caterina

doi:10.1158/1078-0432.ccr-18-2455

Cited by 12 publications

(17 citation statements)

References 5 publications

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“…Furthermore, CAF-derived IL-6 and GM-CSF cooperate to induce trans-differentiation of tumor-resident macrophages to M2 macrophages. 146 – 148 Therefore, the iCAFs are more likely the subpopulation that induces M2 polarization, although this will need to be verified by direct experimental evidence. In addition, the hypoxic tumor microenvironment can also triggers M2-polarized TAMs.…”

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

123

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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

123

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“…We previously reported that treatment of pancreatic cancer heterotopic allografts with anti-BAG3 antibody down-modulated CAF activation and impaired the desmoplastic structure in pancreatic cancer stroma [ 13 ]. In agreement with results in heterotopic allografts, we observed a reduction of the expression of the activation marker α-SMA in CAFs.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in neoplastic cell cytosol it regulates autophagy [ 25 ] and interferes with the Hsp70-mediated delivery of IKKγ [ 9 ] and other anti-apoptotic proteins [ 15 ] to proteasome, sustaining their levels and cell survival, while, being secreted by pancreatic cancer cells, it binds to a specific receptor (BAG3R) on TAMs, triggering the p38- and Akt-dependent release of pro-tumorigenic cytokines and chemokines [ 10 , 11 , 15 ]. In several pancreatic cancer murine models, BAG3 blockade by a monoclonal antibody impairs the activation of TAMs [ 11 , 12 ] and CAFs [ 13 ]. This effect produces a significant reduction of the tumor growth of both MIA PaCa-2 and patient-derived pancreatic cancer xenografts in immunodeficient mice [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Concerted BAG3 and SIRPα blockade impairs pancreatic tumor growth

et al. 2022

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The BAG3- and SIRPα- mediated pathways trigger distinct cellular targets and signaling mechanisms in pancreatic cancer microenvironment. To explore their functional connection, we investigated the effects of their combined blockade on cancer growth in orthotopic allografts of pancreatic cancer mt4–2D cells in immunocompetent mice. The anti-BAG3 + anti-SIRPα mAbs treatment inhibited (p = 0.007) tumor growth by about the 70%; also the number of metastatic lesions was decreased, mostly by the effect of the anti-BAG3 mAb. Fibrosis and the expression of the CAF activation marker α-SMA were reduced by about the 30% in animals treated with anti-BAG3 mAb compared to untreated animals, and appeared unaffected by treatment with the anti-SIRPα mAb alone; however, the addition of anti-SIRPα to anti-BAG3 mAb in the combined treatment resulted in a > 60% (p < 0.0001) reduction of the fibrotic area and a 70% (p < 0.0001) inhibition of CAF α-SMA positivity. Dendritic cells (DCs) and CD8+ lymphocytes, hardly detectable in the tumors of untreated animals, were modestly increased by single treatments, while were much more clearly observable (p < 0.0001) in the tumors of the animals subjected to the combined treatment. The effects of BAG3 and SIRPα blockade do not simply reflect the sum of the effects of the single blockades, indicating that the two pathways are connected by regulatory interactions and suggesting, as a proof of principle, the potential therapeutic efficacy of a combined BAG3 and SIRPα blockade in pancreatic cancer.

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“…The eBAG3‐induced signaling in cells expressing BAG3R involves AKT phosphorylation, 8 which in turn is able to trigger downstream the expression of α‐SMA 19 . To verify the possible activity of eBAG3 on human fibroblasts, NHDF cells were incubated with rBAG3 and the effect on the expression of the fibroblasts' activation marker α‐SMA was then evaluated.…”

Section: Resultsmentioning

confidence: 99%

BAG3 induces α‐SMA expression in human fibroblasts and its over‐expression correlates with poorer survival in fibrotic cancer patients

Marco

Papa²,

Reppucci

et al. 2021

J of Cellular Biochemistry

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Hypoxia and angiogenesis in solid tumors are often strictly linked to the development of fibrotic tissues, a detrimental event that compromises the antitumor immunity. As a consequence, tumor aggressiveness and poor patient prognosis relate to higher incidence of tissue fibrosis and stromal stiffness. The molecular pathways through which normal fibroblasts are converted in cancer‐associated fibroblasts (CAFs) have a central role in the onset of fibrosis in tumor stroma, thus emerging as a strategic target of novel therapeutic approaches for cancer disease. Several studies addressed the role of BAG3 in sustaining growth and survival of cancer cell and also shed light on the different mechanisms in which the intracellular protein is involved. More recently, new pieces of evidence revealed a pivotal role of extracellular BAG3 in pro‐tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues. Here we report further data showing the presence of the BAG3 receptor (Interferon‐induced transmembrane protein [IFITM]‐2) on the plasma membrane of normal dermal fibroblasts and the activity of BAG3 as a factor able to induce the expression of α‐smooth muscle actin and the phosphorylation of AKT and focal adhesion kinase, that sustain CAF functions in tumor microenvironment. Furthermore, in agreement with these findings, bag3 gene expression has been analyzed by high throughput RNA sequencing databases from patients‐derived xenografts. A strong correlation between bag3 gene expression and patients' survival was found in several types of fibrotic tumors. The results obtained provide encouraging data that identify BAG3 as a promising therapeutic target to counteract fibrosis in tumors.

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CAF-Derived IL6 and GM-CSF Cooperate to Induce M2-like TAMs–Letter

Cited by 12 publications

References 5 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

Concerted BAG3 and SIRPα blockade impairs pancreatic tumor growth

BAG3 induces α‐SMA expression in human fibroblasts and its over‐expression correlates with poorer survival in fibrotic cancer patients

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