Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

Abstract

Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease

Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

“…In humans, the disease most commonly affects adolescents, while middle-to-older aged canines are impacted [ 42 , 43 , 44 ]. Histologically, OSA is characterised by transformed bone progenitor cells that produce immature osteoid, while radiographically, it presents as a ‘sunburst’ appearance or triangular appearance (‘Codman’s Triangle’) due to the osteolytic or osteoblastic nature, and the bone lesion’s ability to elevate the periosteal surface, respectively [ 45 , 46 ]. The disease most commonly presents in the metaphyseal region of long bones of the limb such as the femur, tibia or humerus [ 47 ].…”

PRRX1 promotes malignant properties in human osteosarcoma

“…Unfortunately, clinical studies, such as those examining targeted agents, have shown disappointing results and changed little in the last three decades [1] . For the development of novel treatments to improve the prognosis of osteosarcoma patients, further elucidation of the molecular mechanisms that support the invasion and proliferation of osteosarcoma cells is of paramount importance [6] , [7] , [8] , [9] , [10] .…”

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

“…Osteosarcoma is the most common primary bone tumor and is highly malignant [ 1 ]. Neoadjuvant and adjuvant chemotherapy for osteosarcoma has largely remained unchanged since the 1980s, with wide surgical excision and preservation of limb function [ 1 ].…”

“…Osteosarcoma is the most common primary bone tumor and is highly malignant [ 1 ]. Neoadjuvant and adjuvant chemotherapy for osteosarcoma has largely remained unchanged since the 1980s, with wide surgical excision and preservation of limb function [ 1 ]. However, despite such treatment, only 60–70% of patients without clinically evident metastasis at first diagnosis remain alive after 3 years [ 2 ].…”

“…The metastatic process is a multi-stage cascade, whereby cancer characterized by the dissemination of tumor cells with proteolytic activity, enabling the tumor to invade various tissues [ 1 ]. Several different adhesion molecules regulate cancer migration and invasion during the metastatic process, including vascular cell adhesion molecule 1 (VCAM-1), an inducible surface glycoprotein from the immunoglobulin superfamily, which is involved in numerous biological activities [ 6 ].…”