Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Abstract

Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti-IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti-IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti-IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.

Therapeutic Targeting of the IGF Axis

“…There are additional health risks associated with chronic exposure to high circulating IGF-1, including increasing bone fragility. This seems paradoxical given that IGFs are required for normal bone development [76]. However, excess IGF-1 secretion has been shown to compromise bone integrity and microstructure, leading to increased risk of vertebral fracture [77].…”

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

“…In niche formation, BMSCs, osteoblasts, osteoclasts, hematopoietic stem cells (HSCs), monocytes, and pericytes secrete growth factors, and calcium around PCa cells that help PCa cells remain dormant for self-renewal [65,82,83]. Growth factors that are enriched in the tumor microenvironment (TME) include TGF-β, Ca 2+ , hematopoietin, bone morphogenic proteins (BMPs), CXCL12, annexin A2 (ANXA2), and insulin-like growth factor (IGF) [2,82,84,85], among which TGF-β and BMPs play central roles in holding PCa cells in dormancy via the tyrosine-protein kinase receptor, UFO (Axl)/growth arrest specific 6 (Gas6) axis [86,87]. Localized PCa cells are reactivated when the growth suppressors (TGF-β and BMPs) are removed or growth conditions occur.…”

Alpha-Particle Therapy for Multifocal Osteosarcoma: A Hypothesis

“…All three are transmembrane proteins that are upregulated in OST and in osteoblastic bone metastases secondary to cancers other than OST. [47][48][49][50][51] Upon binding to their ligands, these receptors form internalizable complexes. [52][53][54][55][56][57][58][59][60][61] The ligands are retained in the subcellular spaces assuring the retention and decay of 227 Th within a close proximity to the cell's DNA (Fig.…”