Molecular pathogenesis of bone metastases in breast cancer: Proven and emerging therapeutic targets

Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.

Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications

Autosomal dominant osteopetrosis type 2 (ADO2) is a high-density brittle bone disease characterized by bone pain,multiple fractures and skeletal-related events,including nerve compression syndrome and hematological failure.We demonstrated that in mice carrying the heterozygous Clcn7^G213R mutation,whose human mutant homolog CLCN7^G215R affects patients,the clinical impacts of ADO2 extend beyond the skeleton,affecting several other organs.The hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis,associated with high numbers of macrophages and lymphoid infiltrates.Fragmented clinical information in a small cohort of patients confirms extra-skeletal alterations consistent with a systemic disease,in line with the observation that the CLCN7 gene is expressed in many organs.ADO2 mice also show anxiety and depression and their brains exhibit not only perivascular fibrosis but also β-amyloid accumulation and astrogliosis,suggesting the involvement of the nervous system in the pathogenesis of the ADO2 extra-skeletal alterations.Extra-skeletal organs share a similar cellular pathology,confirmed also in vitro in bone marrow mononuclear cells and osteoclasts,characterized by an impairment of the exit pathway of the Clcn7 protein product,ClC7,through the Golgi,with consequent reduced ClC7 expression in late endosomes and lysosomes,associated with high vesicular pH and accumulation of autophagosome markers.Finally,an experimental siRNA therapy,previously proven to counteract the bone phenotype,also improves the extra-skeletal alterations.These results could have important clinical implications,supporting the notion that a systematic evaluation of ADO2 patients for extra-skeletal symptoms could help improve their diagnosis,clinical management,and therapeutic options.

Liquid biopsies in primary and secondary bone cancers

Liquid biopsies are a powerful tool to non-invasively analyze tumor phenotype and progression as well as drug resistance.In the bone oncology field,liquid biopsies would be particularly important to develop,since standard biopsies can be very painful,dangerous(e.g.,when found in proximity to the spinal cord),and hard to collect.In this review,we explore the recent advances in liquid biopsies in both primary(osteosarcoma and Ewing sarcoma)and secondary bone cancers(breast,prostate,and lung cancer-induced bone metastases),presenting their current role and highlighting their unexpressed potential,as well as the barriers limiting their possible adoption,including costs,scalability,reproducibility,and isolation methods.We discuss the use of circulating tumor cells,cell-free circulating tumor DNA,and extracellular vesicles for the purpose of improving diagnosis,prognosis,evaluation of therapy resistance,and driving therapy decisions in both primary and secondary bone malignancies.

How the “seed” prepares the “soil”: the bone/bone marrow pre-metastatic niche

Cancer is one of the leading causes of death in women and men worldwide.The fatal outcome usually occurs after metastatic dissemination,and bone is by far the most common site of metastasis for breast and prostate cancer,the highest incidence neoplasia in women and men,respectively.However,while this is clear,the mechanisms through which the metastatic preference is established is not.An emerging concept in this regard is the pre-metastatic niche(PMN)establishment,i.e.,the process through which tumors can influence the bone microenvironment from the primary site and make it permissive for their engraftment,before they migrate to the blood flow and metastasize.In this review,we discuss key microenvironmental players in the bone/bone marrow PMN,including osteoblasts,osteoclasts,and bone marrow adipocytes.We also describe the known PMN-educating factors,as well as the role of extracellular vesicles as emerging players in the bone/bone marrow PMN.An overview of current therapeutic developments aimed at targeting the bone PMN is also provided.