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1.
Int J Mol Sci ; 22(13)2021 Jun 25.
Article in English | MEDLINE | ID: mdl-34202300

ABSTRACT

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.


Subject(s)
Bone Neoplasms/pathology , Bone Neoplasms/secondary , Bone Resorption/etiology , Bone Resorption/metabolism , Cell Communication , Osteoclasts/metabolism , Osteosarcoma/complications , Osteosarcoma/pathology , Animals , Bone Neoplasms/diagnostic imaging , Bone Remodeling , Bone Resorption/diagnosis , Disease Progression , Disease Susceptibility , Humans , Osteogenesis
2.
J Biol Chem ; 295(27): 9157-9170, 2020 07 03.
Article in English | MEDLINE | ID: mdl-32424040

ABSTRACT

C-type lectins that contain collagen-like domains are known as collectins. These proteins are present both in the circulation and in extravascular compartments and are central players of the innate immune system, contributing to first-line defenses against viral, bacterial, and fungal pathogens. The collectins mannose-binding lectin (MBL) and surfactant protein D (SP-D) are regulated by tissue fibroblasts at extravascular sites via an endocytic mechanism governed by urokinase plasminogen activator receptor-associated protein (uPARAP or Endo180), which is also a collagen receptor. Here, we investigated the molecular mechanisms that drive the uPARAP-mediated cellular uptake of MBL and SP-D. We found that the uptake depends on residues within a protruding loop in the fibronectin type-II (FNII) domain of uPARAP that are also critical for collagen uptake. Importantly, however, we also identified FNII domain residues having an exclusive role in collectin uptake. We noted that these residues are absent in the related collagen receptor, the mannose receptor (MR or CD206), which consistently does not interact with collectins. We also show that the second C-type lectin-like domain (CTLD2) is critical for the uptake of SP-D, but not MBL, indicating an additional level of complexity in the interactions between collectins and uPARAP. Finally, we demonstrate that the same molecular mechanisms enable uPARAP to engage MBL immobilized on the surface of pathogens, thereby expanding the potential biological implications of this interaction. Our study reveals molecular details of the receptor-mediated cellular regulation of collectins and offers critical clues for future investigations into collectin biology and pathology.


Subject(s)
Collectins/metabolism , Endocytosis/physiology , Receptors, Mitogen/genetics , Animals , CHO Cells , Carrier Proteins/metabolism , Collagen/metabolism , Cricetulus , Fibroblasts/metabolism , HEK293 Cells , Humans , Lectins, C-Type , Mannose Receptor , Mannose-Binding Lectin/metabolism , Mannose-Binding Lectins , Membrane Glycoproteins/metabolism , Pulmonary Surfactant-Associated Protein D/metabolism , Receptors, Cell Surface , Receptors, Collagen/metabolism , Receptors, Mitogen/metabolism , Receptors, Urokinase Plasminogen Activator/genetics , Receptors, Urokinase Plasminogen Activator/metabolism
3.
Oncotarget ; 8(27): 44605-44624, 2017 Jul 04.
Article in English | MEDLINE | ID: mdl-28574834

ABSTRACT

A key task in developing the field of personalized cancer therapy is the identification of novel molecular targets that enable treatment of cancers not susceptible to other means of specific therapy. The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers, notably including sarcomas, glioblastomas and subsets of acute myeloid leukemia. In contrast, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells. Functionally, uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its cargo directly into the endosomal-lysosomal system, thus opening a potential route of entry into receptor-positive cells. This combination of specific expression and endocytic function appears well suited for targeting of uPARAP/Endo180-positive cancers by antibody-drug conjugate (ADC) mediated drug delivery. Therefore, we utilized a specific monoclonal antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, which reacts with both the human and the murine receptor, to construct a uPARAP-directed ADC. This antibody was coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin-labile valine-citrulline linker. With this ADC, we show strong and receptor-dependent cytotoxicity in vitro in uPARAP/Endo180-positive cancer cell lines of sarcoma, glioblastoma and leukemic origin. Furthermore, we demonstrate the potency of the ADC in vivo in a xenograft mouse model with human uPARAP/Endo180-positive leukemic cells, obtaining a complete cure of all tested mice following intravenous ADC treatment with no sign of adverse effects. Our study identifies uPARAP/Endo180 as a promising target for novel therapy against several highly malignant cancer types.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Immunoconjugates/pharmacology , Mannose-Binding Lectins/antagonists & inhibitors , Membrane Glycoproteins/antagonists & inhibitors , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Mitogen/antagonists & inhibitors , Animals , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Survival , Disease Models, Animal , Endocytosis , Gene Expression , Humans , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/mortality , Leukemia/pathology , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Molecular Targeted Therapy , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Mitogen/genetics , Receptors, Mitogen/metabolism , Sarcoma/drug therapy , Sarcoma/metabolism , Sarcoma/mortality , Sarcoma/pathology , Tumor Burden/drug effects , Tumor Burden/genetics , Xenograft Model Antitumor Assays
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