Spontaneous Osteoclastogenesis, a risk factor for bone metastasis in advanced luminal A-type breast cancer patients

Introduction: Osteolytic bone metastasis in advanced breast cancer stages are a major complication for patient ' s quality life and a sign of low survival prognosis. Permissive microenvironments which allow cancer cell secondary homing and later proliferation are fundamental for metastatic processes. The causes and mechanisms behind bone metastasis in breast cancer patients are still an unsolved puzzle. Therefore, in this work we contribute to describe bone marrow pre-metastatic niche in advanced breast cancer patients. Results: We show an increase in osteoclasts precursors with a concomitant imbalance towards spontaneous osteoclastogenesis which can be evidenced at bone marrow and peripheral levels. Pro-osteoclastogenic factors RANKL and CCL-2 may contribute to bone resorption signature observed in bone marrow. Meanwhile, expression levels of specific microRNAs in primary breast tumors may already indicate a pro-osteoclastogenic scenario prior to bone metastasis. Discussion: The discovery of prognostic biomarkers and novel therapeutic targets linked to bone metastasis initiation and development are a promising perspective for preventive treatments and metastasis management in advanced breast cancer patients

Spontaneous Osteoclastogenesis, a risk factor for bone metastasis in advanced luminal A-type breast cancer patients

Introduction: Osteolytic bone metastasis in advanced breast cancer stages are a major complication for patient´s quality life and a sign of low survival prognosis. Permissive microenvironments which allow cancer cell secondary homing and later proliferation are fundamental for metastatic processes. The causes and mechanisms behind bone metastasis in breast cancer patients are still an unsolved puzzle. Therefore, in this work we contribute to describe bone marrow pre-metastatic niche in advanced breast cancer patients. Results: We show an increase in osteoclasts precursors with a concomitant imbalance towards spontaneous osteoclastogenesis which can be evidenced at bone marrow and peripheral levels. Pro-osteoclastogenic factors RANKL and CCL-2 may contribute to bone resorption signature observed in bone marrow. Meanwhile, expression levels of specific microRNAs in primary breast tumors may already indicate a pro-osteoclastogenic scenario prior to bone metastasis. Discussion: The discovery of prognostic biomarkers and novel therapeutic targets linked to bone metastasis initiation and development are a promising perspective for preventive treatments and metastasis management in advanced breast cancer patients.Fil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Giorello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Choi, Hosoon. No especifíca;Fil: Dimase, Federico. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Feldman, Leonardo. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Bordenave, Raúl Horacio. Hospital Iriarte; ArgentinaFil: Chudzinski Tavassi, Ana Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Low Oct4 expression in mesenchymal stem cells contributes to the development of the bone marrow pre-metastatic niche in advanced breast cancer patients

The imbalance between osteogenesis and osteoclastogenesis in the bone marrow (BM) microenvironment seems to play an essential role in the establishment of bone metastasis in untreated advanced breast cancer patients (BCP). We have previously found that this lack of balance is produced, among other factors, by a lower self-renewal, proliferation, and osteogenic differentiation capacity of BM-mesenchymal stem cells (MSCs). Mechanisms mediating these characteristic changes remain elusive. Here, we evaluated the expression of the osteoprogenitor marker CD146 (Flow cytometry), telomerase activity (qPCR), telomere length (qPCR), as well as the expression of the pluripotency factors Oct4 and Sox2 (qPCR) in BM-MSCs from clinical stage IIIb BCP (n=8) vs. healthy volunteers (HV; n=8). We found that MSCs from BCP had lower percentage of CD146+ cells (p=0.04), decreased CD146 relative fluorescence index (p=0.002), lower telomerase activity (p=0.04), and shortened telomere length (p=0.002) compared with HV. Moreover, Oct4 and Sox2 expression decreased by 54% (p=0.03) and 72% (p=0.009) in BCP-MSCs, respectively. Interestingly, Oct4 silencing impaired the ability of BM-MSCs to differentiate into osteoblasts (p<0.0001). In conclusion, we found that a low Oct4 expression characterizes the altered BM-MSC phenotype in BCP. This change may explain the loss of osteoprogenitors and the impairment of MSC osteogenic processes, which create an ideal environment for BM metastatic development.Fil: Sanmartin, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Malvicini, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Martinez, Leandro Marcelo. Weill Cornell Medical College; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Feldman, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batagelj, Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Pacienza, Natalia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaBuenos Aires Breast Cancer SymposiumBuenos AiresArgentinaCentro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”Consejo Nacional de Investigaciones Científicas y TécnicasInstituto de Biología y Medicina ExperimentalInstituto de Fisiología, Biología Molecular y NeurocienciasInstituto de Investigaciones en Medicina TraslacionalInstituto de NanosistemasUniversidad AustralUniversidad de Buenos AiresUniversidad Nacional de San Martí

Behaviour of mesenchymal stem cells from bone marrow of untreated advanced breast and lung cancer patients before bone osteolytic metastasis

Tumour cells can find in bone marrow (BM) a niche rich in growth factors and cytokines that promote their self-renewal, proliferation and survival. In turn, tumour cells affect the homeostasis of the BM and bone, as well as the balance among haematopoiesis, osteogenesis, osteoclastogenesis and bone-resorption. As a result, growth and survival factors normally sequestered in the bone matrix are released, favouring tumour development. Mesenchymal stem cells (MSCs) from BM can become tumour-associated fibroblasts, have immunosuppressive function, and facilitate metastasis by epithelial-to-mesenchymal transition. Moreover, MSCs generate osteoblasts and osteocytes and regulate osteoclastogenesis. Therefore, MSCs can play an important pro-tumorigenic role in the formation of a microenvironment that promotes BM and bone metastasis. In this study we showed that BM MSCs from untreated advanced breast and lung cancer patients, without bone metastasis, had low osteogenic and adipogenic differentiation capacity compared to that of healthy volunteers. In contrast, chondrogenic differentiation was increased. Moreover, MSCs from patients had lower expression of CD146. Finally, our data showed higher levels of Dkk-1 in peripheral blood plasma from patients compared with healthy volunteers. Because no patient had any bone disorder by the time of the study we propose that the primary tumour altered the plasticity of MSCs. As over 70 % of advanced breast cancer patients and 30–40 % of lung cancer patients will develop osteolytic bone metastasis for which there is no total cure, our findings could possibly be used as predictive tools indicating the first signs of future bone disease. In addition, as the MSCs present in the BM of these patients may not be able to regenerate bone after the tumour cells invasion into BM/bone, it is possible that they promote the cycle between tumour cell growth and bone destruction.Fil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Hofer, Erica L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Choi, Hosoon. Texas A&M Health Science Center; Estados UnidosFil: Bordenave, Raúl H.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Zonal General de Agudos "Dr. Isidoro G. Iriarte" Quilmes; ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Feldman, Leonardo. Fundacion Favaloro; ArgentinaFil: La Russa, Vincent. Memorial Sloan Kettering Cancer Center; Estados UnidosFil: Caramutti, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Dimase, Federico. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Critical molecular mechanisms that modify bone marrow-mesenchymal stem cell behaviour in advanced breast cancer patients

Most of untreated advanced breast cancer patients (BCP, invasive ductal, stage IIIB) develop osteolytic bone metastasis, due to the existence of a pre-metastatic niche (PMN) that favours extravasa tion, migration, and proliferation of tumor cells. We found that bone marrow (BM) mesenchymal stem cells (MSC) from BCP have lower cloning, proliferation, and osteogenic differentiation capacities than healthy donors (HD) MSC. A conserved pool of functional MSC is essential for preventing the PMN formation.Fil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sanmartin, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Giorello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fernández Vallone, Valeria Beatriz. Humboldt-Universität zu Berlin; AlemaniaFil: Martinez, Leandro Marcelo. Cornell University; Estados UnidosFil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Feldman, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pacienza, Natalia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaReunión Anual de Sociedades de Biociencia 2020Buenos AiresArgentinaSociedad Argentina de Investigación Clínica SAICSociedad Argentina de Inmunología SAISociedad Argentina de Fisiología SAFI

Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer

BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression free survival. RESULTS: After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. CONCLUSIONS: The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285.

Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases

Bone metastasis is an incurable complication of breast cancer affecting 70-80 % of advanced patients. It is a multistep process that includes tumour cell mobilisation, intravasation, survival in the circulation, extravasation, migration and proliferation in the bone marrow/bone. Although novel findings demonstrate the bone marrow microenvironment significance in bone metastatic progression, a majority of studies have focused on end-stage disease and little is known about how the pre-metastatic niche arises in the bone marrow/bone tissues. We demonstrated a significant increase in patients´ peripheral blood plasma ability to induce transendothelial migration of MCF-7 cells compared with healthy volunteers. Moreover, high RANKL, MIF and OPG levels in patients´ peripheral blood could play a role in the intravasation, angiogenesis, survival and epithelial-mesenchymal transition of circulating tumour cells. Also, we observed a significant increase in patients´ bone marrow plasma capacity to induce transendothelial migration of MDA-MB231 and MCF-7 cells compared with healthy volunteers. Furthermore, patients´ bone marrow mesenchymal stem cells could control the recruitment of tumour cells, modifying the MCF-7 and MDA-MB231 cell migration. In addition, we found a significantly higher MDA-MB231 cell proliferation when we used patients´ bone marrow plasma compared with healthy volunteers. Interestingly, PDGF-AB, ICAM-1 and VCAM-1 levels in patients´ bone marrow were significantly higher than the values of healthy volunteers, suggesting that they could be involved in the cancer cell extravasation, bone resorption and cancer cell proliferation. We believe that these results can reveal new information about what alterations happen in the bone marrow of advanced breast cancer patients before bone colonisation, changes that create optimal soil for the metastatic cascade progression.Fil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Choi, Hosoon. Medicine Institute for Regenerative Medicine. Texas A&M University Health Science Center; Estados UnidosFil: Hofer, Erica Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Feldman, Leonardo. Fundacion Favaloro; ArgentinaFil: Bordenave, Raúl Horacio. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Zonal General de Agudos "Dr. Isidoro G. Iriarte" (Quilmes); ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Dimase, Federico. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Rodriguez Villafañe, Ana. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin