Blocking Autophagy in Cancer-Associated Fibroblasts Supports Chemotherapy of Pancreatic Cancer Cells

Zhang, Xianbin; Schönrogge, Maria; Eichberg, Johanna; Wendt, Edgar Heinz Uwe; Kumstel, Simone; Stenzel, Jan; Lindner, Tobias; Jaster, Robert; Krause, Bernd J.; Vollmar, Brigitte; Zechner, Dietmar

doi:10.3389/fonc.2018.00590

Cited by 27 publications

(22 citation statements)

References 34 publications

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“…A short period of neutropenia may indicate a deficient dosage and a lack of lethality . Previous studies have shown that the matrix response produces a physical barrier to defend carcinoma cells from chemotherapy in solid tumors, and inhibiting autophagy in CAFs contributes to the effects of chemotherapy on pancreatic cancer . Stage II‐III GAC patients with the SMA low CD66b low phenotype might benefit from adjuvant chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

et al. 2020

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Background: Emerging evidence indicates that the tumor microenvironment (TME) influences tumor progression through the various cells it contains. Tumor-associated neutrophils (TANs) and cancer-associated fibroblasts (CAFs) are prominent constituents of diverse malignant solid tumors and are crucial in the TME and cancer evolution. However, the relationships and combined prognostic value of these two cell types are not known in gastric adenocarcinoma (GAC). Materials and Methods: In total, 215 GAC patients who underwent curative surgery were enrolled. TANs were assessed by immunohistochemical staining for CD66b, and CAFs were evaluated by immunohistochemical staining for α-smooth muscle actin (α-SMA). Results: The percentages of patients with high-density TANs and CAFs in GAC tissue were 47.9% (103/215) and 43.3% (93/215), respectively. The densities of TANs and CAFs in GAC tissue samples were markedly elevated and independently correlated with GAC clinical outcomes. A strong correlation (R = .348, P < .001) was detected between TANs and CAFs in GAC. The combination of TANs and CAFs produced a more exact outcome than either factor alone. Patients with an α-SMA low CD66b high (hazard ratio [HR] = 1.791; 95% CI: 1.062-3.021; P = .029), α-SMA high CD66b low (HR = 2.402; 95% CI: 1.379-4.183; P = .002), or α-SMA high CD66b high (HR = 3.599; 95% CI: 2.330-5.560; P < .001) phenotype were gradually correlated with poorer disease-free survival than the subset of patients with an α-SMA low CD66b low phenotype. The same results were observed for disease-specific survival in the subgroups.Noticeably, in stage II-III patients with the α-SMA low CD66b low phenotype, an advantage was obtained with postoperative chemotherapeutics, and the risk of a poor prognosis was reduced compared with stage II-III patients with the α-SMA low CD66b high , α-SMA high CD66b low or α-SMA high CD66b high phenotype (HR: 0.260, 95% CI: 0.124-0.542, P < .001 for disease-free survival; and HR: 0.258, 95% CI: 124-0.538, P < .001 for disease-specific survival). |CONG et al.

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Section: Discussionmentioning

confidence: 99%

CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

et al. 2020

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“…Drugs like metformin and gemcitabine are reported to induce autophagy. The combination of chemotherapeutic like α-cyano-4-hydroxycinnamate (CHC) alone and in combination with metformin is reported to hinder autophagic flux in CAFs and hampers tumor cell proliferation, irrespective of chemotherapeutic agents in in vitro and in syngeneic pancreatic cancer model [86].…”

Section: Cancer-associated Fibroblast (Cafs)mentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

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“…Moreover, blocking autophagy in CAFs could supports chemotherapy through proliferation inhibition in pancreatic, oral squamous cell carcinoma and pancreatic adenocarcinoma cancer cells [73–75]. Radiation-induced rescue effect is closely related to radiation-induced bystander effect and describes the phenomenon that irradiated cells derive benefits from feedback signals released from bystander unirradiated cells, then alleviate the harmful radiobiological effects.…”

Section: Introductionmentioning

confidence: 99%

The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer

Yan

Chen

Wang

et al. 2019

J Exp Clin Cancer Res

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Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical trials, such as the pharmacological inhibitor chloroquine or the inducer rapamycin, especially in exploiting its ability to modulate the secretory capability of CAFs to enhance drug delivery or inhibit it to prevent its influence on cancer cell chemoresistance. In this review, we summarize the reports on autophagy in cancer-associated fibroblasts by detailing the mechanism and role of autophagy in CAFs, including the hypoxic-autophagy positive feedback cycle, the metabolic cross-talk between CAFs and tumors induced by autophagy, CAFs secreted cytokines promote cancer survival by secretory autophagy, CAFs autophagy-induced EMT, stemness, senescence and treatment sensitivity, as well as the research of antitumor chemicals, miRNAs and lncRNAs. Additionally, we discuss the evidence of molecules in CAFs that are relevant to autophagy and the contribution to sensitive treatments as a potential target for cancer treatment.

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Blocking Autophagy in Cancer-Associated Fibroblasts Supports Chemotherapy of Pancreatic Cancer Cells

Cited by 27 publications

References 34 publications

CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

Tumor microenvironment complexity and therapeutic implications at a glance

The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer

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Blocking Autophagy in Cancer-Associated Fibroblasts Supports Chemotherapy of Pancreatic Cancer Cells

Cited by 27 publications

References 34 publications

CD66b+ neutrophils and α‐SMA+ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

CD66b+ neutrophils and α‐SMA+ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

Tumor microenvironment complexity and therapeutic implications at a glance

The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer

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CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma

CD66b⁺ neutrophils and α‐SMA⁺ fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma