Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma

Kwon, Hee Jung; Choi, Jung Eun; Kang, Su Hwan; Son, Youlim; Bae, Young Kyung

doi:10.1111/his.13184

Cited by 21 publications

(26 citation statements)

References 33 publications

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“…Tetraspanins contribute to numerous cellular process as cell adhesion, cell activation, or proliferation and have been implicated in several carcinogenous processes such as angiogenesis or metastasis in human cancers . Among them, CD9 was first known as a tumor suppressor but several studies showed its oncogenic and prometastatic functions, suggesting that the different partners of CD9 in TEMs could explain these different roles. In hematological malignancies, CD9 has been mainly studied in acute lymphoblastic leukemia (ALL) where it might promote cancer stem cell‐like properties and dissemination of the disease with CXCR4‐mediated migration .…”

Section: Introductionmentioning

confidence: 99%

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

et al. 2019

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CD9 is a cell surface protein and belongs to the tetraspanin family. Its role in carcinomagenesis has been widely studied in solid tumors but remains controversial, depending on the cancer type. Although CD9 seems to be associated with unfavorable outcome and disease progression in acute lymphoblastic leukemia (ALL), this marker has not yet been studied in acute myeloid leukemia (AML). First, we explored its prognostic role and its association with biological factors in a cohort of 112 AML patients treated with intensive chemotherapy. CD9 was expressed in 40% of AML and was associated with a favorable outcome (event‐free survival and relapse‐free survival) in univariate (P = 0.009 and P = 0.048, respectively) and multivariate (P = 0.004 and P = 0.039, respectively) analyses. Interestingly, CD9 expression was different between the more immature physiologic and AML cells (CD34+CD38−) as it was also expressed in AML on putative leukemic stem cells (LSCs) but not on hematopoietic stem cells (HSCs). Hence, CD9 could be a very relevant marker for minimal residual disease (MRD) monitoring in AML based on LSC targeting.

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Section: Introductionmentioning

confidence: 99%

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

et al. 2019

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“…Studies on human tumor cells reported associations between tetraspanin expression and tumor progression showing both reduced (CD82, CD9) and increased expression (CD151, Tspan8) in various cancer types ( 12 , 15 , 37 – 47 ). In patients with invasive breast cancer, it was shown that CD9 on immune cells was associated with a longer disease free survival, while CD9 expression on the tumor cells showed the opposite effect ( 48 ). The relevance of CD37 in tumor suppression has been recently shown in CD37 −/− mice that spontaneously develop B-cell lymphoma, and in patients with CD37-negative B-cell lymphoma that have poor survival ( 45 , 49 ).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Immunity Is Controlled by Tetraspanin Proteins

Schaper

Spriel

2018

Front. Immunol.

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Antitumor immunity is shaped by the different types of immune cells that are present in the tumor microenvironment (TME). In particular, environmental signals (for instance, soluble factors or cell–cell contact) transmitted through the plasma membrane determine whether immune cells are activated or inhibited. Tetraspanin proteins are emerging as central building blocks of the plasma membrane by their capacity to cluster immune receptors, enzymes, and signaling molecules into the tetraspanin web. Whereas some tetraspanins (CD81, CD151, CD9) are widely and broadly expressed, others (CD53, CD37, Tssc6) have an expression pattern restricted to hematopoietic cells. Studies using genetic mouse models have identified important immunological functions of these tetraspanins on different leukocyte subsets, and as such, may be involved in the immune response against tumors. While multiple studies have been performed with regards to deciphering the function of tetraspanins on cancer cells, the effect of tetraspanins on immune cells in the antitumor response remains understudied. In this review, we will focus on tetraspanins expressed by immune cells and discuss their potential role in antitumor immunity. New insights in tetraspanin function in the TME and possible prognostic and therapeutic roles of tetraspanins will be discussed.

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“…This may be important with respect to CD9 functions as Cd9 −/− transgenic adenocarcinoma mouse prostate (TRAMP) prostate cancer mice displayed increased liver metastases, but no changes to lung metastases [30]. In addition, CD9 is ubiquitously expressed and its anti-cancer functions may be dependent on its expression and interactions with other proteins in exosomes [34], other cell types such as stroma [10], and other organ sites. Therefore, a mammary specific Cd9 knockout mouse model or syngeneic engrafting of Cd9 −/− PyMT tumors into Cd9 +/+ mice may further aid in elucidating the role of CD9 in breast cancer progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Low CD9 expression in primary breast tumors is associated with higher metastatic potential, and CD9 gene expression is commonly downregulated in lymph node metastases compared to primary breast tumors [7,8].Whilst CD9 protein levels are commonly lower in breast cancers [9], which cells are expressing CD9 within tumors and which tumor sub-type is being assessed significantly affects the prognostic outcome of this. For example, patients with invasive luminal A subtype breast cancers had a poorer prognosis if they had high levels of CD9 in cancer cells, whereas patients with luminal B breast cancers had a good prognosis with CD9 protein expression in stromal cells [10]. Moreover, CD9 is overexpressed in osteotropic breast cancer cells and bone metastases compared to primary tumors and visceral metastases [11].…”

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confidence: 99%

Tetraspanin CD9 is Regulated by miR-518f-5p and Functions in Breast Cell Migration and In Vivo Tumor Growth

Bond

Kahl

Brzozowski

et al. 2020

Cancers

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Breast cancer is the most commonly diagnosed and the second leading cause of cancer-related mortality among women worldwide. miR-518f-5p has been shown to modulate the expression of the metastasis suppressor CD9 in prostate cancer. However, the role of miR-518f-5p and CD9 in breast cancer is unknown. Therefore, this study aimed to elucidate the role of miR-518f-5p and the mechanisms responsible for decreased CD9 expression in breast cancer, as well as the role of CD9 in de novo tumor formation and metastasis. miR-518f-5p function was assessed using migration, adhesion, and proliferation assays. miR-518f-5p was overexpressed in breast cancer cell lines that displayed significantly lower CD9 expression as well as less endogenous CD9 3′UTR activity, as assessed using qPCR and dual luciferase assays. Transfection of miR-518f-5p significantly decreased CD9 protein expression and increased breast cell migration in vitro. Cd9 deletion in the MMTV/PyMT mouse model impaired tumor growth, but had no effect on tumor initiation or metastasis. Therefore, inhibition of miR-518f-5p may restore CD9 expression and aid in the treatment of breast cancer metastasis.

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Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma

Cited by 21 publications

References 33 publications

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

Antitumor Immunity Is Controlled by Tetraspanin Proteins

Tetraspanin CD9 is Regulated by miR-518f-5p and Functions in Breast Cell Migration and In Vivo Tumor Growth

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