Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion

Psallidas, Ioannis; Stathopoulos, Georgios T.; Maniatis, Nikolaos A.; Magkouta, Sophia; Moschos, Charalampos; Karabela, Sophia P.; Kollintza, Androniki; Simoes, Davina Camargo Madeira; Kardara, Matina; Vassiliou, Spyridoula; Papiris, Spyros; Roussos, Charis; Kalomenidis, Ioannis

doi:10.1038/onc.2012.57

Cited by 52 publications

(61 citation statements)

References 40 publications

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“…To trigger these events, tumour cells execute pro-inflammatory and pro-angiogenic transcriptional programmes which are controlled, at least in part, by transcription factors nuclear factor (NF)-κB [27] and signal transducer and activator of transcription (STAT) 3 [28,29]. Autocrine tumour necrosis factor (TNF), interleukin (IL)-6 and osteopontin (OPN) participate in positive feedback loops regulating tumour NF-κB/STAT3 activation to promote MPE [29][30][31]. In addition, tumour-derived mediators, including vascular endothelial growth factor (VEGF), C-C-motif chemokine ligand (CCL) 2 and TNF, directly stimulate inflammatory cell influx and/or vascular changes [31][32][33][34].…”

Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Malignant pleural effusion: from bench to bedside

et al. 2016

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Malignant pleural effusion (MPE) is a common but serious condition that is related with poor quality of life, morbidity and mortality. Its incidence and associated healthcare costs are rising and its management remains palliative, with median survival ranging from 3 to 12 months. During the last decade there has been significant progress in unravelling the pathophysiology of MPE, as well as its diagnostics, imaging, and management. Nowadays, formerly bed-ridden patients are genotyped, phenotyped, and treated on an ambulatory basis. This article attempts to provide a comprehensive overview of current advances in MPE from bench to bedside. In addition, it highlights unanswered questions in current clinical practice and suggests future directions for basic and clinical research in the field. @ERSpublications This review provides up to date knowledge for malignant pleural effusion covering aspects from bench to bedside http://ow.ly/10w7vN

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Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Malignant pleural effusion: from bench to bedside

et al. 2016

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“…Interestingly, Balb/c mice features high serum osteopontin levels compared with C57BL/6 mice, 37 and 4T1 cells secrete less osteopontin compared with LLC and MC38 cells (1 vs. 20-40 mg/mL/10 6 cells/24 h, respectively), likely rendering host osteopontin important in 4T1 cell metastasis, 15 but not in our hands. Similarly, we measured elevated levels of host osteopontin in MPE 16 as compared with the bloodstream in our study (300 vs. 70 ng/mL, respectively), making host osteopontin important in MPE, 16 but not in the work presented here. In our hands, the pulmonary endothelium did not express osteopontin and the bulk of local osteopontin was delivered by metastatic tumor cells, rendering tumor-expressed osteopontin pivotal for lung colonization.…”

Section: Discussionmentioning

confidence: 65%

“…34,35 Our negative results from osteopontin-deficient mice are different from findings from breast cancer and malignant pleural effusion (MPE) models where host osteopontin was important. 15,16 However, the different results can be reconciled and convey mechanistic implications: The different models employed in these studies feature divergent anatomic and cellular compartmentalization of osteopontin expression and different osteopontin expression patterns by tumor cells. 36 Since osteopontin impacts late-stage metastasis, the local levels of tumor-and host-delivered osteopontin in the incipient metastatic niche are likely critical.…”

Section: Discussionmentioning

confidence: 99%

“…This notion is of special importance for neoplasms where osteopontin biology is cardinal and TRP53 mutations frequent, such as malignant pleural mesothelioma. 16,[41][42][43] Third, sSPP1 is identified as the key osteopontin isoform that promotes lung metastasis across tumor types. To this end, overexpression of the corresponding transcript Spp1is4 exerted a far stronger pro-metastatic impact on naturally osteopontindeficient B16F10 cells, compared with the transcript Spp1is2 that corresponds to iSPP1.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] Osteopontin has been linked with enhanced tumor progression and metastasis by modulating cell-cell interactions, by activating signal transduction pathways, by altering gene expression, and by promoting tumor cell survival. [13][14][15][16][17][18][19][20] Interestingly, the diverse effects of SPP1 vary between cell types and target organs of metastasis, depending on which signaling pathways are activated and which isoforms of the protein are expressed. 16,21,22 Despite significant efforts, a comprehensive understanding of the functions of cancer-and host-originated SPP1 isoforms during pulmonary metastasis is elusive.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

et al. 2016

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The lungs are ubiquitous receptacles of metastases originating from various bodily tumors. Although osteopontin (SPP1) has been associated with tumor dissemination, the role of its isoforms in lung-directed metastasis is incompletely understood. We employed syngeneic mouse models of spontaneous and induced lung-targeted metastasis in C57BL/6 mice competent and deficient in both Spp1 alleles. Tumorderived osteopontin expression was modulated using either stable anti-Spp1 RNA interference, or forced overexpression of intracellular and secreted Spp1 isoforms. Identified osteopontin's downstream partners were validated using lung adenocarcinoma cells conditionally lacking the Trp53 gene and Ccr2-deficient mice. We determined that host-derived osteopontin was dispensable for pulmonary colonization by different tumor types. Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors. As new ways to target osteopontin signaling are becoming available, the cytokine may constitute an important therapeutic target against pulmonary involvement by cancers of other organs. KEYWORDSC-C-motif chemokine ligand 2; inflammation and cancer; secreted phosphoprotein 1; spontaneous lung metastasis; tumor-related protein 53

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Single‐cell RNA sequencing captures patient‐level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions

Whitfield,

Berthelet,

Mangiola

et al. 2023

Clinical & Translational Med

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BackgroundMalignant pleural effusions (MPEs) are a common complication of advanced cancers, particularly those adjacent to the pleura, such as lung and breast cancer. The pathophysiology of MPE formation remains poorly understood, and although MPEs are routinely used for the diagnosis of breast cancer patients, their composition and biology are poorly understood. It is difficult to distinguish invading malignant cells from resident mesothelial cells and to identify the directionality of interactions between these populations in the pleura. There is a need to characterize the phenotypic diversity of breast cancer cell populations in the pleural microenvironment, and investigate how this varies across patients.MethodsHere, we used single‐cell RNA‐sequencing to study the heterogeneity of 10 MPEs from seven metastatic breast cancer patients, including three Miltenyi‐enriched samples using a negative selection approach. This dataset of almost 65 000 cells was analysed using integrative approaches to compare heterogeneous cell populations and phenotypes.ResultsWe identified substantial inter‐patient heterogeneity in the composition of cell types (including malignant, mesothelial and immune cell populations), in expression of subtype‐specific gene signatures and in copy number aberration patterns, that captured variability across breast cancer cell populations. Within individual MPEs, we distinguished mesothelial cell populations from malignant cells using key markers, the presence of breast cancer subtype expression patterns and copy number aberration patterns. We also identified pleural mesothelial cells expressing a cancer‐associated fibroblast‐like transcriptomic program that may support cancer growth.ConclusionsOur dataset presents the first unbiased assessment of breast cancer‐associated MPEs at a single cell resolution, providing the community with a valuable resource for the study of MPEs. Our work highlights the molecular and cellular diversity captured in MPEs and motivates the potential use of these clinically relevant biopsies in the development of targeted therapeutics for patients with advanced breast cancer.

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Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion

Cited by 52 publications

References 40 publications

Malignant pleural effusion: from bench to bedside

Malignant pleural effusion: from bench to bedside

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

Single‐cell RNA sequencing captures patient‐level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions

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