CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease

Johnson, Sarah K.; Stewart, James; Bam, Rakesh; Qu, Pingping; Barlogie, Bart; Rhee, Frits van; Shaughnessy, John D.; Epstein, Joshua; Yaccoby, Shmuel

doi:10.1182/blood-2014-02-555813

Cited by 24 publications

(39 citation statements)

References 45 publications

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Section: Discussionsupporting

confidence: 82%

“…These results suggest that, in addition to inhibition of osteoblastogenesis (Yaccoby, 2010b), MM also inhibits formation of small adipocytes, a cell population that is closely associated with red marrow and haematopoiesis (Scheller et al, 2015). Our findings also indicate that, similar to other mesenchymal cell factors, such as decorin, CYR61, and adiponectin (Li et al, 2008;Fowler et al, 2011;Johnson et al, 2014), IGFBP2 functions as a MM-restraining factor that is suppressed during disease progression. We found the expression patterns of MSC genes in FLs from all risk groups were similar to those of MSCs in BM of patients with HR MM and that expression of most MSC genes was lower in FLs and in HR MM than in LR MM.…”

Section: Discussionmentioning

confidence: 51%

“…Recent studies suggest that MM induces proliferation and expansion of MSCs (Frassanito et al, 2014;Noll et al, 2014), but other studies showed that MM cells elicit a premature senescence phenotype in MSCs (Andre et al, 2013). Osteoblasts and osteocytes are suppressed, particularly in areas of MM involvement (Bataille et al, 1991;Giuliani et al, 2012) and factors highly produced by these cells [e.g., CCN1 (Johnson et al, 2014), decorin (Li et al, 2008)] restrain MM growth.…”

Section: Resultsmentioning

confidence: 99%

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Mesenchymal stem cells gene signature in high‐risk myeloma bone marrow linked to suppression of distinct IGFBP2‐expressing small adipocytes

et al. 2018

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Summary Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age‐matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin‐like growth factor‐binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under‐expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co‐expression was detected in a subset of small adipocytes. Co‐culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1‐mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

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Mesenchymal stem cells gene signature in high‐risk myeloma bone marrow linked to suppression of distinct IGFBP2‐expressing small adipocytes

et al. 2018

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“…Interestingly, CCN1 is higher in random BM biopsies compared to focal myeloma lesions. CCN1 overexpression in myeloma cells also decreases tumor growth and osteolytic lesion formation in vivo [135]. Therefore, the authors of this study concluded that CCN1 may act as a protective mechanism by bone marrow cells against myeloma.…”

Section: Ccn Familymentioning

confidence: 86%

“…CCN1 is also implicated to play a role in metastasis of prostate cancer cells, although other studies indicate that CCN1 has contradictory functions in these cells by promoting both proliferation and TRAIL-induced apoptosis [134]. In myeloma, one study found that CCN1 in bone marrow mesenchymal cells is positively associated with longer time of progression from pre-malignant disease to overt myeloma and increased progression-free and overall survival of myeloma patients [135]. Interestingly, CCN1 is higher in random BM biopsies compared to focal myeloma lesions.…”

Section: Ccn Familymentioning

confidence: 99%

Matricellular proteins as regulators of cancer metastasis to bone

Trotter

Yang

2016

Matrix Biology

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Metastasis is the major cause of the death in cancer patients, and a frequent site of metastasis for many cancers is the bone marrow. Therefore, understanding the mechanisms underlying the metastatic process is necessary for future prevention and treatment. The tumor microenvironment is now known to play a role in the metastatic cascade, both at the primary tumor and in metastatic sites, and includes both cellular and non-cellular components. The extracellular matrix (ECM) provides structural support and signaling cues to cells. One particular group of molecules associated with the ECM, known as matricellular proteins, modulate multiple aspects of tumor biology, including growth, migration, invasion, angiogenesis and metastasis. These proteins are also important for normal function in the bone by regulating bone formation and bone resorption. Recent studies have described a link between some of these proteins and metastasis of various tumors to the bone. The aim of this review is to summarize what is currently known about matricellular protein influence on bone metastasis. Particular attention to the contribution of both tumor cells and non-malignant cells in the bone has been given.

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CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3β/cyclinD1 signal pathway in Myeloma Bone Disease

Yan

Liu

et al. 2019

Cancer Medicine

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Backgrounds: Myeloma-related bone disease (MBD) is a common complication of multiple myeloma (MM), which can both decrease life quality and influence the prognosis of the patients. We have found that CCN1 stimulated proliferation and differentiation of osteoblasts in MM in vitro and in vivo, while its mechanism still remains unknown. Method: Bone marrow mononuclear cells were collected from MM patients and differentiated into the osteoblasts. After co-culture with CCN1 in vitro, the intracellular signaling antibody array and western blot were performed to explore the signaling pathway. Furthermore, GSK3β inhibitor TWS119 was used to check the pathway of CCN1 might have on osteoblasts in vitro. Results: For the protein array kit, the expressions of GSK3β, 4E-BP1, and PTEN are decreased in CCN1 group. For western blots, the CCN1 group also has lower expression comparing to the control group in PTEN (P = .031). Meanwhile p-AKT and cyclinD1 levels have increased in the CCN1 group (P = .002, P = .039). After adding TWS119 as another group, western blot was performed again to verify the pathway. For upstream proteins PTEN and p-AKT, TWS119 group has higher expression level compared to that in CCN1 group (P = .003, P = .001). And for downstream protein cyclinD1, TWS119 group also presented higher level than the control group (P = .02). CCN1 could have almost the same effect on GSK3β as the specific inhibitor TWS119 had. Conclusions: CCN1 can stimulate osteoblasts through PTEN/AKT/GSK3β/cy-clinD1 pathway in MBD, which has the potential to be a novel therapy of MBD.

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CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease

Abstract: Key Points CYR61/CCN1 is a bone marrow microenvironmental biomarker for myeloma progression and for transformation of MGUS and asymptomatic disease to overt myeloma. CCN1 reduces myeloma bone disease and tumor growth and is a potential therapeutic target for myeloma.

Cited by 24 publications

References 45 publications

Mesenchymal stem cells gene signature in high‐risk myeloma bone marrow linked to suppression of distinct IGFBP2‐expressing small adipocytes

Mesenchymal stem cells gene signature in high‐risk myeloma bone marrow linked to suppression of distinct IGFBP2‐expressing small adipocytes

Matricellular proteins as regulators of cancer metastasis to bone

CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3β/cyclinD1 signal pathway in Myeloma Bone Disease

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