Functions of Thrombospondin-1 in the Tumor Microenvironment

Kaur, Sukhbir; Bronson, Steven M.; Pal-Nath, Dipasmita; Miller, Thomas W.; Soto-Pantoja, David R.; Roberts, D. A.

doi:10.3390/ijms22094570

Cited by 100 publications

(74 citation statements)

References 249 publications

(340 reference statements)

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“…It is now recognized that targeting appropriate components of the tumor microenvironment may be of particular interest in developing innovative anti-tumor therapeutic approaches. Thrombospondin-1 (TSP-1) is a 450 kDa homotrimeric glycoprotein acknowledged as a key matricellular protein within the tumor microenvironment [ 1 , 2 , 3 ]. Due to its multi-modular organization, TSP-1 can bind a wide variety of ligands, including other ECM components, extracellular proteases, growth factors and cell-surface receptors, such as LRP-1, integrins, CD36 and CD47 [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity

Jeanne

Sarazin

Charlé

et al. 2021

Cancers

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TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2’s ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity.

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Section: Introductionmentioning

confidence: 99%

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity

Jeanne

Sarazin

Charlé

et al. 2021

Cancers

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“…In the case of TSP-1, as mentioned in introduction, majority of available literature indicate the role of tumor microenvironment [13], especially TSP-1/CD47 interaction seems to play key role [12,14]. In addition, in premalignant lung tumors TSP-1 participates in suppression of Kras-induced tumorigenesis [42].…”

Section: Discussionmentioning

confidence: 96%

“…It is not easy to explain, why the decreased levels of these two markers: TSP-1 and BMP-4 might promote tumor development, because the role in cancer progression of these two analyzed markers remains unclear. A number of studies confirm anti-tumor functions of TSP-1 and BMP-4 [13,17,[39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Solid tumors consist not only of active proliferating carcinoma cells but also of other cell types that create the proper microenvironment promoting tumor progression [12]. TSP-1 in the tumor microenvironment influences the biology of multiple cell types associated with tumor growth and metastatic potential [13]. TSP-1 binds to the cell surface receptor CD47, known also as integrin-associated protein, through the globular carboxy-terminal cell-binding domain.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Thrombospondin-1 and Bone Morphogenetic Protein-4 Serum Levels as Potential Indices of Advanced Stage Lung Cancer

Kosacka

Dyła

Chaszczewska-Markowska

et al. 2021

JCM

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Introduction: Lung cancer belongs to the most common carcinoma worldwide and is the leading cause of cancer-related death. Bone morphogenetic protein-4 (BMP-4) is extracellular signaling molecule involved in many important processes, including cell proliferation and mobility, apoptosis and angiogenesis. Thrombospondin-1 (TSP-1) belongs to the extracellular matrix proteins. It participates in the cell-to-cell and cell-to-matrix interactions and thus plays important role in tumor microenvironment for cancer development and metastasis formation. Aim: To investigate serum levels of TSP-1 and BMP-4 together with BMP-4 polymorphism in lung cancer patients. Material and Methods: A total of 111 patients (76 men) with newly diagnosed lung cancer, including 102 patients with non-small cell lung cancer and 9 patients with small-cell lung cancer. Advanced stage of lung cancer was diagnosed in 99 (89%) of patients: stage IV—in 48, stage IIIB—in 33, stage IIIA—in 18 patients; there were six patients with stage II and six patients with stage I. The control group consisted of 61 healthy persons. In all the subjects, serum levels of BMP-4 and TSP-1 were measured by ELISA. With a Real-Time PCR system genotyping of BMP-4 was performed. Results: BMP-4 and TSP-1 serum levels were significantly lower in the patients with lung cancer than in the controls (TSP-1:10,109.2 ± 9581 ng/mL vs. 11,415.09 ± 9781 ng/mL, p < 0.05; BMP-4: 138.35 ± 62.59 pg/mL vs. 226.68 ± 135.86 pg/mL p < 0.001). In lung cancer patients TSP-1 levels were lower in advanced stages (9282.07 ± 4900.78 ng/mL in the stages III-IV vs. 16,933.60 ± 6299.02 ng/mL in the stages I-II, p < 0.05) and in the patients with than without lymph nodes involvement (10,000.13 ± 9021.41 ng/mL vs. 18,497.75 ± 12,548.25 ng/mL, p = 0.01). There was no correlation between TSP-1 and BMP-4 serum levels. BMP-4 gene polymorphism did not influence the results of the study. Conclusion: Decreased levels of TSP-1 and BMP-4 may serve as potential indices of lung cancer, with additional importance of low TSP-1 level as a marker of advanced stage of the disease.

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“…Soluble Thrombospondin-1 (TSP1), released in the SASP, is involved in Ras-induced senescence ( 198 ). Moreover, TSP1 released by tumor cells binds CD47 on NK cells inhibiting its activity ( 199 ). CD47 is described as a relevant modulator of NK cell function in virus infection ( 200 ).…”

Section: Acquisition Of Therapy Induced-senescence (Tis) After Chemotherapy and Its Impact On Immune Cellsmentioning

confidence: 99%

Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

Etxebeste-Mitxeltorena

Rincón-Loza

Martín-Antonio

2021

Front. Immunol.

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Adoptive cellular immunotherapy using chimeric antigen receptor (CAR)-modified T cells and Natural Killer (NK) cells are common immune cell sources administered to treat cancer patients. In detail, whereas CAR-T cells induce outstanding responses in a subset of hematological malignancies, responses are much more deficient in solid tumors. Moreover, NK cells have not shown remarkable results up to date. In general, immune cells present high plasticity to change their activity and phenotype depending on the stimuli they receive from molecules secreted in the tumor microenvironment (TME). Consequently, immune cells will also secrete molecules that will shape the activities of other neighboring immune and tumor cells. Specifically, NK cells can polarize to activities as diverse as angiogenic ones instead of their killer activity. In addition, tumor cell phagocytosis by macrophages, which is required to remove dying tumor cells after the attack of NK cells or CAR-T cells, can be avoided in the TME. In addition, chemotherapy or radiotherapy treatments can induce senescence in tumor cells modifying their secretome to a known as “senescence-associated secretory phenotype” (SASP) that will also impact the immune response. Whereas the SASP initially attracts immune cells to eliminate senescent tumor cells, at high numbers of senescent cells, the SASP becomes detrimental, impacting negatively in the immune response. Last, CAR-T cells are an attractive option to overcome these events. Here, we review how molecules secreted in the TME by either tumor cells or even by immune cells impact the anti-tumor activity of surrounding immune cells.

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Functions of Thrombospondin-1 in the Tumor Microenvironment

Cited by 100 publications

References 249 publications

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity

Decreased Thrombospondin-1 and Bone Morphogenetic Protein-4 Serum Levels as Potential Indices of Advanced Stage Lung Cancer

Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

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