CD47 promotes T-cell lymphoma metastasis by up-regulating AKAP13-mediated RhoA activation

Kitai, Yuichi; Ishiura, Marie; Saitoh, Kunimasa; Matsumoto, Naoki; Owashi, Kimiya; Yamada, Shunsuke; Muromoto, Ryuta; Kashiwakura, Jun‐ichi; Oritani, Kenji; Matsuda, Tadashi

doi:10.1093/intimm/dxab002

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…Another study conducted in non-small cell lung cancer (NSCLC) tumor tissues and cell lines demonstrated that CD47 is overexpressed in these tumors and is significantly associated with clinical staging, lymph node metastases, and distant metastases (Zhao et al 2016 ). These findings were supported by an animal study demonstrating that CD47 contributes to the formation and metastasis of T-cell lymphoma in vivo (Kitai et al 2021 ). It is noteworthy to acknowledge that CD47 blockade has demonstrated remarkable success in the treatment of hematological malignancies (Hai et al 2022 ).…”

Section: Discussionmentioning

confidence: 53%

A comprehensive analysis of CD47 expression in various histological subtypes of soft tissue sarcoma: exploring novel opportunities for macrophage-directed treatments

Benesova,

Capkova,

Ozaniak

et al. 2024

J Cancer Res Clin Oncol

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Purpose The CD47 molecule, often referred to as the “do not eat me” signal, is frequently overexpressed in tumor cells. This signaling pathway limits phagocytosis by macrophages. Our objective was to determine CD47 abundance in various soft tissue sarcomas (STS) to investigate whether it could serve as a potential evasion mechanism for tumor cells. Additionally, we aimed to assess the prognostic value of CD47 expression by examining its association with different clinicopathological factors. This study aimed to elucidate the significance of CD47 in the context of emerging anti-tumor targeting approaches. Methods In this retrospective study, formalin-fixed paraffine-embedded (FFPE) tumor tissues of 55 treatment-naïve patients were evaluated by immunohistochemistry for the abundance of CD47 molecule on tumor cells. The categorization of CD47 positivity was as follows: 0 (no staining of tumor cells), 1 + (less than 1/3 of tumor area positive), 2 + (between 1/3 and 2/3 of tumor area positive), and 3 + (more than 2/3 of tumor area positive for CD47). Next, we compared CD47 abundance between different tumor grades (G1–3). We used Kaplan–Meier survival curves with log-rank test to analyze the differences in survival between patients with different CD47 expression. Moreover, we performed Cox proportional hazards regression model to evaluate the clinical significance of CD47. Results CD47 is widely prevalent across distinct STS subtypes. More than 80% of high grade undifferentiated pleiomorphic sarcoma (UPS), 70% of myxofibrosarcoma (MFS) and more than 60% of liposarcoma (LPS) samples displayed a pattern of moderate-to-diffuse positivity. This phenomenon remains consistent regardless of the tumor grade. However, there was a tendency for higher CD47 expression levels in the G3 group compared to the combined G1 + G2 groups when all LPS, MFS, and UPS were analyzed together. No significant associations were observed between CD47 abundance, death, and metastatic status. Additionally, high CD47 expression was associated with a statistically significant increase in progression-free survival in the studied cohort of patients. Conclusion This study highlights the potential of the CD47 molecule as a promising immunotherapeutic target in STS, particularly given its elevated expression levels in diverse sarcoma types. Our data showed a notable trend linking CD47 expression to tumor grade, while also suggesting an interesting correlation between enhanced abundance of CD47 expression and a reduced hazard risk of disease progression. Although these findings shed light on different roles of CD47 in STS, further research is crucial to assess its potential in clinical settings.

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Section: Discussionmentioning

confidence: 53%

A comprehensive analysis of CD47 expression in various histological subtypes of soft tissue sarcoma: exploring novel opportunities for macrophage-directed treatments

Benesova,

Capkova,

Ozaniak

et al. 2024

J Cancer Res Clin Oncol

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“…RhoA overexpression has been associated with a significantly reduced disease-free and distant metastasis-free survival in cervical squamous cell carcinoma [ 49 ]. A facilitatory role for RhoA in inducing a more aggressive phenotype has been observed also in other malignancies, such as for instance lung adenocarcinoma [ 50 ], ovarian carcinoma [ 51 ] and lymphoma [ 52 ].…”

Section: Discussionmentioning

confidence: 97%

The V2 receptor antagonist tolvaptan counteracts proliferation and invasivity in human cancer cells

Marroncini

Anceschi

Naldi

et al. 2022

J Endocrinol Invest

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Purpose Hyponatremia, the most frequent electrolyte alteration in clinical practice, has been associated with a worse prognosis in cancer patients. On the other hand, a better outcome has been related to serum sodium normalization. In vitro studies have shown that low extracellular sodium promotes cancer cells proliferation and invasiveness. Tolvaptan, a selective vasopressin receptor type 2 (V2) antagonist, has been effectively used in the last decade for the treatment of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. A few in vitro data suggested a direct role of tolvaptan in counteracting cancer progression, so far. The aim of this study was to evaluate the effect and the mechanism of action of tolvaptan in cell lines from different tumours [i.e. colon cancer (HCT-8), hepatocarcinoma (HepG2), neuroblastoma (SK-N-AS)]. Methods and results First, we showed that these cell lines express the V2 receptor. Tolvaptan significantly reduced cell proliferation with an IC50 in the micromolar range. Accordingly, reduced levels of cAMP, of the catalytic α subunit of PKA, and a reduced pAKT/AKT ratio were observed. Tolvaptan effectively inhibited cell cycle progression, whereas it induced apoptotis. Furthermore, it reduced cell invasiveness. In particular, anchorage-independent growth and the activity of collagenases type IV were blunted in the three cell lines. Accordingly, tolvaptan counteracted the RhoA/ROCK1–2 pathway, which has a pivotal role in regulating cell movement. Conclusions Overall, these findings indicate that tolvaptan effectively inhibits tumour progression in vitro. Further studies should clarify whether the V2 receptor might be considered a possible target in anti-cancer strategies in the future.

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“…Cancer cells may evade immune detection and clearance by expressing CD47, a cell surface protein that has been proposed to function as a "don't eat me" signal (52,53). Antibodies or peptides against CD47 or its receptor, signal regulatory protein α (SIRPα), can stimulate an engulfment response either by blocking the "don't eat me signal" or by opsonizing the cancer cell for phagocytosis (54)(55)(56)(57)(58). To adapt this approach to our experimental system, we challenged HL-60 neutrophils with Ramos B lymphoma target cells in the absence or presence of anti-CD47 blockade.…”

Section: Gβ 4 Deficiency Enhances Phagocytic Responses Against a Wide...mentioning

confidence: 99%

Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells

Winer,

Settle,

Yakimov

et al. 2024

Sci. Immunol.

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Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ 4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ 4 -deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ 4 . In Gβ 4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.

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CD47 promotes T-cell lymphoma metastasis by up-regulating AKAP13-mediated RhoA activation

Cited by 8 publications

References 26 publications

A comprehensive analysis of CD47 expression in various histological subtypes of soft tissue sarcoma: exploring novel opportunities for macrophage-directed treatments

A comprehensive analysis of CD47 expression in various histological subtypes of soft tissue sarcoma: exploring novel opportunities for macrophage-directed treatments

The V2 receptor antagonist tolvaptan counteracts proliferation and invasivity in human cancer cells

Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells

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