CD38 in cancer-associated fibroblasts promotes pro-tumoral activity

Baruch, Bar Ben; Mantsur, Einav; Franco‐Barraza, Janusz; Blacher, Eran; Cukierman, Edna; Stein, Reuven

doi:10.1038/s41374-020-0458-8

Cited by 29 publications

(15 citation statements)

References 46 publications

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“…Inflammatory cells such as neutrophil granulocytes and macrophages contribute to angiogenesis and tumor progression in vivo by differentiating to a tumor-supporting phenotype [ 52 , 63 , 64 ]. Fibroblasts support the development of a protumor, proangiogenic environment, e.g., through the secretion of platelet-derived growth factor (PDGF), fibroblasts growth factor (FGF), epithelial growth factor (EGF) and also hepatic growth factor (HGF), by extracellular matrix proteins, and fibroblast activation protein (FAP) [ 65 , 66 ]. Thus, successful tumor vascularization is the result of the fine-tuned interaction between numerous cell types in the tumor stroma that needs to be reflected in a 3D in vitro model in order to analyze the efficacy of antiangiogenic and antitumor therapies.…”

Section: Discussionmentioning

confidence: 99%

Recapitulating the Angiogenic Switch in a Hydrogel-Based 3D In Vitro Tumor-Stroma Model

2021

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To ensure nutrient and oxygen supply, tumors beyond a size of 1–2 mm3 need a connection to the vascular system. Thus, tumor cells modify physiological tissue homeostasis by secreting inflammatory and angiogenic cytokines. This leads to the activation of the tumor microenvironment and the turning of the angiogenic switch, resulting in tumor vascularization and growth. To inhibit tumor growth by developing efficient anti-angiogenic therapies, an in depth understanding of the molecular mechanism initiating angiogenesis is essential. Yet so far, predominantly 2D cell cultures or animal models have been used to clarify the interactions within the tumor stroma, resulting in poor transferability of the data obtained to the in vivo situation. Consequently, there is an abundant need for complex, humanized, 3D models in vitro. We established a dextran-hydrogel-based 3D organotypic in vitro model containing microtumor spheroids, macrophages, neutrophils, fibroblasts and endothelial cells, allowing for the analysis of tumor–stroma interactions in a controlled and modifiable environment. During the cultivation period of 21 days, the microtumor spheroids in the model grew in size and endothelial cells formed elongated tubular structures resembling capillary vessels, that appeared to extend towards the tumor spheroids. The tubular structures exhibited complex bifurcations and expanded without adding external angiogenic factors such as VEGF to the culture. To allow high-throughput screening of therapeutic candidates, the 3D cell culture model was successfully miniaturized to a 96-well format, while still maintaining the same level of tumor spheroid growth and vascular sprouting. The quantification of VEGF in the conditioned medium of these cultures showed a continuous increase during the cultivation period, suggesting the contribution of endogenous VEGF to the induction of the angiogenic switch and vascular sprouting. Thus, this model is highly suitable as a testing platform for novel anticancer therapeutics targeting the tumor as well as the vascular compartment.

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Section: Discussionmentioning

confidence: 99%

Recapitulating the Angiogenic Switch in a Hydrogel-Based 3D In Vitro Tumor-Stroma Model

2021

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“…Mechanistically, the knockout of CD38 decreased both CAF numbers and tumor growth. CD38 could increase fibroblastic migration towards tumor cells and enhance melanoma invasive behavior ( 22 ). In pancreatic ductal adenocarcinoma, CD38 was obvious increased on peripheral PD-1 + CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

CD38 Multi-Functionality in Oral Squamous Cell Carcinoma: Prognostic Implications, Immune Balance, and Immune Checkpoint

Ding

et al. 2021

Front. Oncol.

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BackgroundCD38 belongs to the ribosyl cyclase family and is expressed on various hematological cells and involved in immunosuppression and tumor promotion. Although targeting CD38 antibodies has been approved for treatment of multiple myeloma, the function of CD38 in solid tumor, oral squamous cell carcinoma (OSCC) etc., has not been investigated.MethodsThis retrospective study included 92 OSCC samples and analyzed the spatial distribution of CD38 by immunohistochemistry (IHC). The values of diagnosis and prognosis of CD38 were evaluated. Additionally, 53 OSCC preoperative peripheral blood samples were used to be analyzed by flow cytometry. Tumor Immune Estimation Resource (TIMER) and cBioPortal databases were used to study CD38 level in various tumors and its correlation with tumor immune microenvironment in head and neck squamous cell carcinoma (HNSCC).ResultsCD38 ubiquitously presented in tumor cells (TCs), fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs). Patients with highly expressed CD38 in TCs (CD38TCs) had higher TNM stage and risk of lymph node metastasis. Upregulation of CD38 in FLCs (CD38FLCs) was significantly associated with poor WPOI. Escalated CD38 in TILs (CD38TILs) led to higher Ki-67 level of tumor cells. Moreover, patients with enhanced CD38TCs were susceptible to postoperative metastasis occurrence, and those with highly expressed CD38TILs independently predicted shorter overall and disease-free survival. Strikingly, patients with highly expressed CD38TILs, but not CD38TCs and CD38FLCs, had significantly lower CD3+CD4+ T cells and higher ratio of CD3−CD16+CD56+NK cells. The imbalance of immune system is attributed to dysregulated immune checkpoint molecules (VISTA, PD-1, LAG-3, CTLA-4, TIGIT, GITR) as well as particular immune cell subsets, which were positively correlated with CD38 expression in HNSCC.ConclusionCD38 is a poor prognostic biomarker for OSCC patients and plays a vital role in governing immune microenvironment and circulating lymphocyte homeostasis. Co-expression between CD38 and immune checkpoint molecules provides new insight into immune checkpoint therapy.

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“…Isatuximab (also named SAR650984 or Sarclisa ® ) is a chimeric IgG1 antibody developed by ImmunoGen and Sanofi-Aventis capable of targeting CD38 (15)(16)(17)(18)(19)(20). CD38 is a cell surface antigen with ectoenzymatic activity overexpressed on malignant plasma cells, which are a type of B cells responsible for antibody production and secretion in the body (21). Therefore, this antigen can be a considerable target in the immunotherapy of multiple myeloma.…”

Section: Isatuximabmentioning

confidence: 99%

Monoclonal Antibodies (mAbs) Approved for Cancer Treatment in the 2020s

et al. 2021

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: Monoclonal antibodies are one of the most eminent types of immunotherapeutics that have taken over the biopharmaceutical market because they are approved for a wide range of cancers, either blood-based malignancies or solid tumors, and also non-cancer indications, from migraine to viral infections. Due to their wide applicability as immunotherapeutics, countless biopharmaceutical companies try to be in the competition by developing monoclonal antibodies and advancing into clinical trials with them. Since the approval of the first monoclonal antibodies, the speed of their discovery and approval for medical use have been rather incremental, so that the progress of this market has been anticipated to increase in the current decade. Herein, we take a look at some of the monoclonal antibodies, which have been approved for clinical use in the current decade, so far. Moreover, we underline the encouraging results from the clinical trials that led to the approval of these immunotherapeutics.

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CD38 in cancer-associated fibroblasts promotes pro-tumoral activity

Cited by 29 publications

References 46 publications

Recapitulating the Angiogenic Switch in a Hydrogel-Based 3D In Vitro Tumor-Stroma Model

Recapitulating the Angiogenic Switch in a Hydrogel-Based 3D In Vitro Tumor-Stroma Model

CD38 Multi-Functionality in Oral Squamous Cell Carcinoma: Prognostic Implications, Immune Balance, and Immune Checkpoint

Monoclonal Antibodies (mAbs) Approved for Cancer Treatment in the 2020s

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