Increased Dickkopf-1 expression in breast cancer bone metastases

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases

The combined targeting of VEGF-A and VEGF receptors inhibits breast cancer bone metastases in mice

Bone and mineral researc

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in sera of NET patients collected retrospectively (n=88) and prospectively (n=87) using Roche-Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF were elevated in patients with pancreatic NETs (pNETs) as compared to control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as prognostic parameter and therapeutic target

Calcium channel ITPR2 and mitochondria-ER contacts promote cellular senescence and aging

International audienceCellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging