IGF-1 and IGF-1R push osteosarcoma progression through subsequent malignant transformation, proliferation, attenuated susceptibility to apoptosis, and the differentiation of a prone to metastasis phenotype [72,73,74]. Notably, the IGF signaling mediators have now been recognized as biomarkers for primary osteosarcoma detection [75]. A distinct correlation between IGF-IR downstream pathways and osteosarcoma disease progression seems to have been identified. The downstream PI3K/AKT pathway was over-activated during primary osteosarcoma development and pulmonary metastasis, whereas the RAS/MAPK pathway seems to contribute to later stages of pulmonary dissemination [72]. Furthermore, it has been shown that IGFBP5, the most profuse bone IGFBP stored in bone, attenuates tumor growth and human osteosarcoma metastasis [76]. IGF-IR expression has been highly correlated with ABC subfamily G member2 (ABCG2) expression in a cohort of osteosarcoma patients under 10 [77]. As ABCG2 bestows resistance to anticancer drugs [78], these data suggest that the two proteins in combination can be utilized as prognostic factors/therapy determinants.

IGF-1 gene polymorphisms were investigated for the association of risks and outcomes of osteosarcomas. Five single nucleotide polymorphisms (SNPs) of IGF-1 (e.g., SNPs like rs6214, rs6218, rs35767, rs5742612, and rs5742714) were genotyped. Out of all tested SNPs, rs6218 proved to have a predictive role for osteosarcoma’s susceptibility and progression. Moreover, this SNP was associated with a later stage and elevated risk of osteosarcoma metastasis [79]. Furthermore, an exclusive nuclear localization of IGF-1R was associated with progression-free survival and overall survival in osteosarcoma patients treated with IGF-1R Ab therapy [80].

Notably, osteosarcoma, in contrast with other pediatric tumors [30], exhibits a high degree of mutational diversity and copy number variability [75,81]. Indeed, 7–14% of osteosarcoma cases exhibit mutations in IGF signaling genes (IGF1R, IGF1, IGF2R, and IGFBP5). Thus, even taking into account intratumor heterogeneity, these data indicate that taking advantage of anomalies in the osteosarcoma genome could offer novel therapeutic strategies [82].

IGF-signaling facilitates chondrosarcoma pathogenesis. Thus, treatment of human chondrosarcoma cells with IGFBP3 or IGF inhibitors enhanced their apoptosis rate, whereas mice expressing Gli2 presented fewer tumors upon IGF-2 downregulation. Therefore, Ho et al. suggest that IGF signaling-dependent apoptosis mediates chondrocytes’ malignant transformation [83].

The genetic polymorphisms in IGF-1 pathway members have also been correlated with elevated risk and poor prognosis of conventional chondrosarcoma patients in Chinese populations. Thus, IGF-IR rs2016347 polymorphisms were associated with the risk of lung metastasis of CHS [84].

Notably, since EWS tumor cells express both IGF-IR and IGF-1, an autocrine loop enhances EWS progression [85]. Moreover, the inhibition of EWS-FLI1 fusion protein decreased IGF-1 and impaired the IGF-1/IGF-1R signaling correlated with increased EWS cell apoptosis, reduced migration, and repressed tumor xenograft growth in a mouse model [86]. Another study focused on EWS cell lines’ high expression of focal adhesion kinase (FAK) transcript and potential interaction with IGF-IR. A dual inhibitor of FAK and IGF-IR, TAE226, was tested along with PF-562,271 as a combination inhibitor of FAK and proline-rich tyrosine kinase 2. TAE226 inhibited the cell growth of various EWS cell lines. The creation of FAK- and IGF-IR- deficient EWS cells induced dysregulation of different signaling pathways. Indeed, TAE226 induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. In EWS mouse models, TAE226 was demonstrated to inhibit the local growth of primary tumors and hinder metastasis. Furthermore, the combination of TAE226 and chemotherapy agents showed that TAE226 could exhibit a synergistic effect with conventional chemotherapy and be possibly beneficial for EWS relapse and metastatic patients [87]. Moreover, a recent study demonstrated that CIC-DUX4 Ewing’s sarcoma, an aggressive and often fatal high-grade childhood sarcoma, metastasizes to the lung, utilizing an autocrine IGF-IR/AKT signaling axis [88].

Thus, a deeper understanding of the IGF-signaling molecular facets is obligatory for developing new therapies involving these molecules.

The ECM is a network mainly consisting of collagens, proteoglycans (PGs), glycoproteins, and glycosaminoglycans such as hyaluronic acid (HA). It has the role of a plastic scaffold that bestows physical support to cells within the tissue and regulates the bioactivities of growth factors and cytokines in a time- and location-dependent manner [94]. Aberrant ECM contributes to the stromal cells’ reprogramming and facilitates tumor cell’ growth and dissemination [89,91,95].

In the last couple of decades, the crucial role of the ECM, the non-cellular section of the TME, has been acknowledged in cancer pathogenesis. Previous efforts in classifying the disease and therapy development had focused on the cellular compartment [96]. However, more recent developments have demonstrated the urgent need to understand the ECM component for tumor characterization and efficient therapy development [89,97].

Bone sarcoma extracellular matrices exhibit striking characteristics. Thus, osteosarcoma osteoid is an organic partly mineralized network that mainly consists of type I collagen, glycoproteins, and PGs [98]. The osteoid’s structural components participate in signaling pathways correlated with specific pathogenic phenotypes of bone [99,100]. Indeed, it has been shown that the small leucine-rich proteoglycans (SLRPs), functionally involved in normal bone development and homeostasis [101], mediate various osteosarcoma cell functions [102,103]. Notably, transcriptional analysis of paired normal bone and osteosarcoma samples demonstrated significant alternations regarding mediators of extracellular matrix degradation and collagen biosynthesis [104]. As recently discussed by Cui et al., an increase in the expression of major ECM components, including collagens (I, III, IV, and V), fibronectin, laminin, and the PGs (biglycan and lumican), has been determined in osteosarcoma compared to normal bone samples [99]. The HA-binding PG, versican, is likewise overexpressed in osteosarcoma tissues relative to healthy bone tissue and facilitates osteosarcoma cell migration [105]. Considering the ECM as a crucial regulator of tumor progression [100] has allowed the identification of specific molecules of the tumor osteoid as putative therapeutic targets [99].

Chondrosarcoma cells are characterized by intense production of cartilage-like ECM, rich in collagen type II and proteoglycans [26,106,107], with different expression patterns compared to normal tissue [108,109]. Notably, somatic changes of the collagen 2A1 gene were identified in 19.3% of chondrosarcoma and 31.7% of enchondroma tumor cohort cases [110]. Interestingly, a fusion between activin receptor 2A and fibronectin 1 was detected in 57% of synovial chondromatosis cases and in 75% of chondrosarcoma secondary to synovial chondromatosis, showing that fibronectin1 and/or AVCR2A gene rearrangements are present in both benign and malignant synovial chondromatosis, with a higher incidence in malignant disease [111].

Normal chondrocytes predominantly synthesize collagen types II, IX, X, and XI and characteristic proteoglycans, depending on their differentiation state [112]. The fact that the cartilaginous-like matrix production by chondrosarcoma cells is so intensive may indicate they originate from multipotent mesenchymal stem cells, which differentiate along the chondrocytic lineage. Interestingly, despite the malignant transformation, chondrosarcoma cells continue to express some molecules that characterize normal tissue [112,113,114].

Regarding radiotherapy and conventional chemotherapy, chondrosarcoma is characterized as a resistant lesion [115] due to the tumor’s specific hallmarks. Chondrosarcoma tumor tissue, like hyaline, is characterized by a dense ECM with poor blood and lymph vascularity, on which a low percentage of dividing cells is embedded. Thus, the ECM forms a physical semi-permeable barrier, inhibiting cytotoxic agents reaching their target, i.e., chondrosarcoma cells, while reduced blood circulation creates severe chronic hypoxia [116]. Moreover, the Schwan chondrosarcoma ECM disturbance by modifying the synthesis of ECM components, mainly PGs, attenuates this tumor growth [117]. The participation of non-cellular TEM components required during sarcoma progression and their interaction with IGF-effectors has not been systematically investigated.