lactoferrin and Bone-Neoplasms

Osteosarcoma (OS) is one the most common primary malignancies of the bone in children and young adults with high metastasis. The use of non-toxic naturally derived compounds is one of present strategies in OS therapy to reduce secondary effects and chemo-resistance. Lactoferrin (LF), a transferrin protein derived from milk, currently appears to be an anticancer agent. However, its suppressive effects on OS have not been fully investigated. Therefore, we aimed to examine the molecular mechanism underlying the inhibitory effects of bovine LF (bLF) on OS. OS cell lines (NOS1, U2OS, MG63, and 143B) and an osteoblastic (ST2) were treated with bLF. Effects of bLF on OS-cell proliferation and migration were examined by proliferation and wound-healing assays. Expression levels of low-density-lipoprotein-receptor-related protein 1 (LRP1) and cytokines including interleukin-1 beta (IL-1β), IL-6, and receptor-activator of nuclear factor kappa-Β ligand (RANKL) were measured using western blotting. Osteoclast formation was examined by co-culture of 143B, ST2, and bone marrow cells. We found that bLF down-regulated IL-1β, IL-6, and RANKL expression and suppressed phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 in 143B cells; bLF also drastically suppressed 143B-activated RANKL production in ST2 cells. This may have contributed to the reduction in the number of differentiated osteoclasts. Taken together, these data reveal that bLF down-regulates NF-κB to attenuate proliferation, migration, and bone resorption in OS and the OS-microenvironment. This study provides new findings and the precise underlying mechanisms of the inhibitory effects of bLF on OS. bLF can be a possible therapeutic agent for OS patients.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Cattle; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Interleukin-1beta; Interleukin-6; Lactoferrin; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; NF-kappa B; Osteoblasts; Osteoclasts; Osteogenesis; Osteosarcoma; RANK Ligand; Tumor Microenvironment

By immunohistochemistry, lactoferrin (LF) has been extensively investigated in human neoplastic tissues; moreover, LF is able to promote bone growth in a murine model. Until now, no systematic studies on human osteocartilagineous fetal samples have been performed in comparison to corresponding neoplastic specimens to verify if LF may represent an oncofetal marker in this field of pathology. By a monoclonal antibody (clone 1A1; Biodesign International; w.d. 1:75) the distribution pattern of LF in bones of 25 human fetal tissues (8-34 gestation weeks), 10 adults (47-82 years) and 30 cartilage as well as 27 bone tumours (9-76 years) was analyzed. LF was encountered in 23/57 cases of osteocartilagineous tumors and namely in 10/10 giant cell tumours, 5/7 osteoid osteomas, 3/3 chondroblastomas, 3/3 chondromyxoid fibromas, 1/1 myeloma, 1/1 adamantinoma. No LF immunoexpression was detected in osteosarcomas, chondrosarcomas, ossifying fibromas, osteochondroma and enchondromas. In embryo-fetal tissues, LF immunoreactivity was localized in mesenchymal cells as well as in chondroblasts at the 8th gestational week and in immature osteocytes and osteoblasts up to the 18th gestation week, with a considerable decrease by the 24th week. No LF expression was found in any bone district since the 30th and up to the 34th week of gestation as well as in corresponding adult samples. Our findings indicate a role for LF as a bone growth regulator in the early phases of the human endochondral ossification, although the hypothesis of LF as oncofetal marker appears questionable in bone tumours.

Topics: Adolescent; Aged; Aged, 80 and over; Biomarkers, Tumor; Bone Neoplasms; Cartilage; Child; Female; Fetus; Humans; Immunohistochemistry; Lactoferrin; Male; Middle Aged; Neoplasms, Connective Tissue; Young Adult

Lactoferrin (Lf) is an 80-kDa basic glycoprotein, a member of the transferrin family of iron-binding proteins. Lf immunoreactivity has been extensively investigated in many neoplastic tissues. Recently, Lf expression was documented in the osteoblastic lineage of bone-forming tumors as well as in osteoblasts of fetal bone.. Lactoferrin (Lf) immunoexpression was investigated in 30 human cartilage-forming tumors [15 enchondromas, 6 osteochondromas, 3 chondroblastomas (CBL), 3 chondrosarcomas, and 3 chondromyxoid fibromas (CMF)] as well as in human normal bone specimens and cartilaginous tissues obtained at autopsy from 5 adults and 3 fetuses.In addition, the immunohistochemical expression of Ki-67 antigen was analyzed on parallel sections from the same specimens. Quantification of Lf immunoreactivity was performed by using an intensity distribution (ID) score.. Lf immunoexpression with a variable ID score was encountered exclusively in 3 of 3 chondroblastomas and in 3 of 3 chondromyxoid fibromas. Lf immunoreactivity in these tumors, in clear contrast with the Lf absence in enchondromas, osteochondromas, and chondrosarcomas, may suggest a different histogenesis of the former. In agreement with this histogenetic origin, we detected Lf in the chondroblasts and osteoblasts within the fetal tissue, whereas no immunoreactivity was found in the corresponding adult cells. No significant associations were found between the Lf immunoexpression and the Ki 67 LI of the tumors of our series.. The presence of Lf in neoplastic cells of CBL and CMF, as well as in fetal cartilaginous tissue, may reflect a less mature phenotype of these tumors.

Topics: Adolescent; Adult; Aged; Bone and Bones; Bone Neoplasms; Cartilage; Case-Control Studies; Child; Chondroblastoma; Female; Fibroma; Humans; Immunohistochemistry; Ki-67 Antigen; Lactoferrin; Male; Middle Aged; Young Adult