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NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.

ABSTRACT: Patients with breast cancer are often afflicted by bone metastases, while the establishment and growth of bone metastases depend on interaction between cancer cells and the host environment. Moreover, osteoblasts, which play a vital role in cancer cells survival and colonization, can form an osteogenic niche in early stage of bone metastases. Also, it is widely accepted that there is a genetic determinant during bone metastases. Nephronectin (NPNT) is an extracellular matrix protein which has shown biological activities in breast cancer metastases and osteoblasts differentiation. But the role of NPNT in mediating breast cancer bone metastases remains elusive. In the present study, we revealed that up regulation of NPNT is associated with incidence of bone metastases. What's more, NPNT could significantly enhance the tumor cell clone formation but not proliferation and migration. We further demonstrated that NPNT significantly enhance osteoblast differentiation and tumor adhesion. Thus, we proposed that cancer secreted NPNT may be a novel marker with potential value of prediction and diagnosis of breast cancer bone metastases.

SUBMITTER: Wang D

PROVIDER: S-EPMC6303384 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.

Wang Dongsheng D Zhao Chenglong C Gao Liangliang L Wang Yao Y Gao Xin X Tang Liang L Zhang Kun K Li Zhenxi Z Han Jing J Xiao Jianru J

Journal of bone oncology 20180927

Patients with breast cancer are often afflicted by bone metastases, while the establishment and growth of bone metastases depend on interaction between cancer cells and the host environment. Moreover, osteoblasts, which play a vital role in cancer cells survival and colonization, can form an osteogenic niche in early stage of bone metastases. Also, it is widely accepted that there is a genetic determinant during bone metastases. Nephronectin (NPNT) is an extracellular matrix protein which has sh ...[more]

PMID: 30591862

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Project description:ContextImmunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination.ObjectiveTo determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer.Design, setting, and patientsFrom May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study.InterventionsAll 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results.Main outcome measuresOverall survival (primary end point) and disease-free survival (a secondary end point).ResultsOf 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis.ConclusionAmong women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival.Trial registrationclinicaltrials.gov Identifier: NCT00003854.

Project description:Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone.The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases.The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the potential of metabolomic profiles for risk assessment and early detection and the signalling pathways controlling the metastatic tumour microenvironment. There is substantial synergy between the four projects and it is hoped that this integrated program of research will advance our understanding of key aspects of bone metastases from breast cancer to improve the prevention, prediction, detection, and treatment of these lesions.

Project description:The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in "metastatic niches," special microenvironments that are thought to regulate cancer cell colonization and dormancy as well as tumor progression and subsequent development into overt metastases. Precise location and composition of this "metastatic niche" remain poorly defined. However, it is thought to include an "endosteal niche" that is composed of key bone cells that are derived from both, hematopoietic stem cells (osteoclasts), and mesenchymal stromal cells (osteoblasts, fibroblasts, adipocytes). Our knowledge of how osteoclasts drive the late stage of the disease is well-established. In contrast, much less is known about the interaction between osteogenic cells and disseminated tumor cells prior to the initiation of the osteolytic phase. Recent studies suggest that mesenchymal-derived cells, including osteoblasts and fibroblasts, play a key role during the early stages of breast cancer bone metastasis such as tumor cell homing, bone marrow colonization, and tumor cell dormancy. Hence, elucidating the interactions between breast cancer cells and mesenchymal-derived cells that drive metastasis progression could provide novel therapeutic approaches and targets to treat breast cancer bone metastasis. In this review we discuss evidences reporting the interaction between tumor cells and endosteal niche cells during the early stages of breast cancer bone metastasis, with a particular focus on mesenchymal-derived osteoblasts and fibroblasts.

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NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.

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NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.

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