Pediatric cancer—pathology and microenvironment influence: a perspective into osteosarcoma and non-osteogenic mesenchymal malignant neoplasms

Abstract

Pediatric cancer remains the leading cause of disease-related death among children aged 1–14 years. A few risk factors have been conclusively identified, including exposure to pesticides, high-dose radiation, and specific genetic syndromes, but the etiology underlying most events remains unknown. The tumor microenvironment (TME) includes stromal cells, vasculature, fibroblasts, adipocytes, and different subsets of immunological cells. TME plays a crucial role in carcinogenesis, cancer formation, progression, dissemination, and resistance to therapy. Moreover, autophagy seems to be a vital regulator of the TME and controls tumor immunity. Autophagy is an evolutionarily conserved intracellular process. It enables the degradation and recycling of long-lived large molecules or damaged organelles using the lysosomal-mediated pathway. The multifaceted role of autophagy in the complicated neoplastic TME may depend on a specific context. Autophagy may function as a tumor-suppressive mechanism during early tumorigenesis by eliminating unhealthy intracellular components and proteins, regulating antigen presentation to and by immune cells, and supporting anti-cancer immune response. On the other hand, dysregulation of autophagy may contribute to tumor progression by promoting genome damage and instability. This perspective provides an assortment of regulatory substances that influence the features of the TME and the metastasis process. Mesenchymal cells in bone and soft-tissue sarcomas and their signaling pathways play a more critical role than epithelial cells in childhood and youth. The investigation of the TME in pediatric malignancies remains uncharted primarily, and this unique collection may help to include novel advances in this setting.

Introduction

Pediatric cancer is diagnosed in more than 14,000 U.S. children (0–19 years) per year and in the twenty-first century, it remains the leading cause of disease-related death among children aged 1–14 years [1]. A few risk factors have been conclusively identified, including exposure to pesticides, high-dose radiation, and specific genetic syndromes, but the etiology underlying most events remains unknown. It is now well-recognized that neoplasms co-evolve with the tumor microenvironment (TME), which includes stromal cells, vasculature, fibroblasts, adipocytes, and different subsets of immunological cells. TME plays a crucial role in carcinogenesis, cancer formation, progression, dissemination, and resistance to therapy. Moreover, autophagy seems to be a vital regulator of the TME and controls tumor immunity. Autophagy is an evolutionarily conserved intracellular process. It enables the degradation and recycling of long-lived large molecules or damaged organelles using the lysosomal-mediated pathway. The multifaceted role of autophagy in the complicated neoplastic TME may depend on a specific context. Autophagy may function as a tumor-suppressive mechanism during early tumorigenesis by eliminating unhealthy intracellular components and proteins, regulating antigen presentation to and by immune cells, and supporting anti-cancer immune response. On the other hand, dysregulation of autophagy may contribute to tumor progression by promoting genome damage and instability. Finally, autophagy in TME stromal cells supplying nutrients to neoplastic cells may fuel growth in established neoplasms [2]. In this collection, we aim to gather contributions dealing with pediatric oncogenesis and papers targeting the role of autophagy and microenvironment in pediatric cancer. This perspective provides an assortment of regulatory substances that influence the features of the TME and the metastasis process. Mesenchymal cells in bone and soft-tissue sarcomas and their signaling pathways play a more critical role than epithelial cells in childhood and youth. The investigation of the TME in pediatric malignancies remains mostly uncharted. The highlighted discoveries primarily focus on genes that have been deregulated and are involved with processes such as cell adhesion, migration, and the spread of tumor cells. The involvement of these processes in developing a mesenchymal phenotype remains intriguing. It should be further explored, particularly regarding the epithelial-to-mesenchymal transition in epithelial malignancies. Various regulatory chemicals are impacting the characteristics of the TME and the process of metastasis [3, 4]. Priority is given to the signaling pathways that regulate the biology of mesenchymal cells in bone and soft-tissue malignant mesenchymal neoplasms (sarcomas) occurring in children and youth, as opposed to the epithelial cells, which are more commonly engaged in neoplasms in adults [5]. The exploration of the tumor microenvironment in pediatric cancers remains largely unexplored. The emphasized findings generally center around genes that have undergone deregulation and are implicated in processes such as cell adhesion, migration, and tumor cell dissemination. The role of these mechanisms in forming a mesenchymal phenotype and the spread of cancer is further investigated concerning the epithelial-to-mesenchymal transition (EMT) in epithelial tumors. The impact of cell plasticity on tumor activity is increasingly being acknowledged. Sarcomas are a diverse collection of tumors that present significant hurdles in terms of local recurrence and tumor dissemination, even with aggressive multimodal therapy. The ongoing research aims to identify and understand the molecular pathways responsible for spreading cancer cells to other body parts. Exploring the regulatory effects of structural components and non-malignant cell types that infiltrate the tumor is essential. Pediatric cancers often have a relatively low number of mutations, but they frequently have repeated chromosomal abnormalities [6]. Pathognomonic fusion genes are already being identified in the diagnostic routine for relevant sarcoma subtypes. Additionally, there is a correlation between the status of fusion genes and a poorer prognosis among non-metastatic patients [7]. Genetic and epigenetic alterations in tumor cells play a crucial role in tumor growth and can impact the tumor microenvironment.

Several studies have demonstrated how activated non-malignant mesenchymal cells of the stroma efficiently control matrix stiffness and display contractile and pro-invasive cell behavior [8] and, significantly, how these activities impact medication effectiveness and metastasis [9]. Nevertheless, much research on the tumor microenvironment has focused on epithelial entities that occur in maturity, such as breast carcinomas. Children’s mesenchymal tumors exhibit fundamental distinctions, and the role of non-neoplastic cells in these sarcomas is not well clarified. Without therapy, activated stromal cells are less prone to developing separate compartments, a characteristic commonly observed in epithelial malignancies. Alternatively, they mingle with tumor cells, immune cells, and other cell types within a pseudocapsule around the tumor or maybe aid in creating endothelial tubes during angiogenesis. The necessity of their structural support in advancing sarcoma has not been well examined, and the lack of distinct markers for non-malignant stromal cells in mesenchymal tumors adds complexity to these investigations. The regulation of metastatic dissemination of pediatric malignancies by the TME is still a developing area of investigation. Childhood sarcomas commonly consist of mesenchymal neoplasms, such as osteogenic sarcoma, primitive neuroectodermal tumor or Ewing sarcoma, and rhabdomyosarcoma. The prognosis of these neoplasms is generally favorable in comparison to numerous sarcomas in adults, while the issue of metastatic spread remains essential. Osteosarcoma primarily arises from skeletal tissue and is the tumorous subtype in which the neoplastic microenvironment has been extensively studied. Ewing sarcoma originates in either the bone or soft tissue. At the same time, rhabdomyosarcoma is a type of soft-tissue sarcoma that exhibits characteristics of skeletal muscle with evidence of a myogenic program.

Sarcomas

Bone sarcomas typically exhibit pain, but soft-tissue sarcomas commonly present as painless masses. A detectable mass may or may not be existent in skeletal neoplasms. Constitutional symptoms, such as fatigue, weight loss, or widespread signs of inflammation accompanied by fever, are infrequently seen in cases where the tumors are sizable and have undergone necrosis [1]. Occasionally, the disease is transmitted upon diagnosis with clearly visible metastases. Rhabdomyosarcomas and Ewing sarcomas are classified as high-grade neoplasms, whereas osteosarcomas can exhibit high-grade or low-grade characteristics. The staging of tumors is determined using either the TNM system or the musculoskeletal society system. In the case of rhabdomyosarcoma, the grouping system based on clinical staging is used [10, 11].

Approximately 75–90% of juvenile sarcomas originate as a localized illness. However, it is expected that micrometastases are present in nearly all instances. This phenomenon is exemplified in the historical survival statistics of patients who did not undergo chemotherapy. In these cases, major surgery was found to be effective in controlling the cancer locally, but it was associated with a low overall survival rate [12]. The three primary categories of pediatric sarcomas exhibit a comparable pattern of metastasis, with hematogenous dissemination being the conventional pathway of propagation. The lungs are the primary site for metastasis, followed by the bones and bone marrow. Infrequently seen locations for rhabdomyosarcomas include lymph nodes, viscera, and soft tissues [13]. The prevalence of micrometastatic illness in high-grade pediatric sarcomas indicates that the mechanisms responsible for the spread of tumor cells are active at the initial phases of the disease. Contemporary treatment protocols involve administering systemic chemotherapy at an early stage to eliminate microscopic metastatic illness. This is done with the local removal of the primary tumor and extensive metastases, when possible. Neoadjuvant chemotherapy is commonly administered to patients to treat local illnesses. Following surgery, patients typically get further cycles of chemotherapy [14, 15]. Radiation therapy is obviously administered in patients exhibiting surgical margins, which are inadequate. Alternatively, it is used to locally control radiosensitive neoplasms, such as Ewing sarcomas and rhabdomyosarcomas, when the underlying tumor cannot be operated on. Identifying tumor-specific chromosomal translocations is often valuable for diagnosing pediatric mesenchymal neoplasms [16]. EWS-ETS gene fusion variations are present in Ewing sarcomas, while the predominant fusion genes linked to alveolar rhabdomyosarcoma are PAX3–FOXO1 and PAX7–FOXO1. The two primary subtypes of rhabdomyosarcoma, namely the alveolar subtype, which is more aggressive, can generally be differentiated using contemporary techniques, with a few exceptions. Despite embryonal rhabdomyosarcomas usually occurring sooner in the developing process than the alveolar subtype, they are still clinically and molecularly similar to fusion gene-negative alveolar rhabdomyosarcomas [17]. The outcome of pediatric sarcoma is contingent upon various criteria, such as the dimensions and location of the initial tumor, as well as the age of the patient [18]. The initial disease burden is of utmost importance in this setting, as children who have confined disease at presentation have a significantly more favorable prognosis compared to those with evident tumor dissemination. The primary determinant of patient outcome concerning treatment is the response to chemotherapy. In cases of bone sarcomas, the extent of necrosis following neoadjuvant treatment is commonly assessed [18, 19]. There are multiple histological methods available [1]. Individuals who do not respond well to treatment have a worse chance of recovering from cancer and are classified, based on commonly accepted standards, as those with less than 90% tumor necrosis caused by chemotherapy. Another significant aspect of treatment is the level of quality assurance reached after the examination of surgical margins [20].

Cell migration and cell adhesion

Cell migration refers to the process by which cells move from one location to another within an organism. Metastatic dissemination, conversely, is the spread of cancer cells from the primary tumor to other parts of the body. Upon the initiation of metastasis, tumor cells embark on a complex series of steps, during which their ability to adapt to unfamiliar tissue microenvironments becomes crucial for survival. There are still numerous uncertainties regarding the selection mechanisms that occur throughout the evolution of diseases, specifically in cases when only specific sarcoma cells can reach distant organs and effectively metastasize. The subsequent conversation centers around the flexibility of mesenchymal cells and the cell adhesion molecules that play a role in cell migration and metastasis. It is worth mentioning that the characteristics of mesenchymal qualities in sarcoma are controlled by various signaling pathways involved in development. A recent study conducted by others has discussed some of these pathways [21]. Cell migration can be classified into two main types: collective cell migration, which occurs in epithelial malignancies, and individual cell migration, which happens in sarcoma. Sarcoma mesenchymal cell migration can occur individually or in chains. It is generally controlled by the extracellular matrix (ECM), where different integrins and proteases play major roles. Cadherins, which create adherens junctions, significantly facilitate direct cell–cell interactions in multicellular organisms. Mesenchymal adherens junctions are anticipated to have a shorter duration than the epithelial equivalent, and their stability is partially governed by endocytosis and modulation of the cytoskeleton. Downregulation of E-cadherin is a crucial step in the cellular process of epithelial-to-mesenchymal transition (EMT). At the same time, its overexpression is associated with the mesenchymal to epithelial transition (MET) during the formation of distant metastasis. Osteosarcoma has been observed to undergo a mesenchymal to amoeboid transition (MAT) while migrating via endothelial cells [22]. A recent assessment of mesenchymal features in epithelial tumors found that a partial EMT was uncovered to be profitable for the tumor-initiating ability. However, drug resistance reached a plateau and remained constant when the EMT program was further activated [23]. The effectiveness of invasiveness was highest when there was a robust activation of EMT, resulting in the migration of individual cells rather than the typical migration of multicellular carcinoma cells. The process of EMT in sarcoma is inherently less apparent. However, it is established that the expression of E-cadherin also contributes to the inhibition of anchorage-independent growth and spheroid formation [24]. Claudin-1, a protein that forms tight junctions, is an epithelial differentiation marker that can be identified in sarcoma [25] as well as other epithelial differentiation markers, such keratins [26–32]. It has been demonstrated that epithelial markers in sarcomas are associated with a better prognosis for patients as identified by the meta-analysis of Wang et al. [33]. It may seem counterintuitive, but research has demonstrated that the deliberate activation of mesenchymal-associated adhesion molecules can hinder the movement and spread of cells in osteosarcoma while promoting bone metastasis in osteosarcoma and Ewing sarcoma [34, 35]. Nevertheless, typical osteoblasts exhibit a significant expression of cadherin-11 and N-cadherin, which are crucial in regulating cell function and differentiation. Hence, a TME specific to a particular subtype may elucidate why decreased levels are believed to play a significant role in advancing osteosarcoma and its spread to other parts of the body [36]. Cadherin switching and activating N-cadherin, an EMT marker, are linked to transforming malignant cells derived from epithelial tissues into a mesenchymal phenotype. This transformation is characterized by alterations in cell morphology and the acquisition of migratory and invasive capabilities. Analogous pathways have also been documented in mesenchymal cancers. For instance, activating N-cadherin and alpha9-integrin promotes the invasion of cells in rhabdomyosarcoma through a mechanism that relies on Notch signaling [37]. The Notch signaling pathway is a developmental mechanism that has a role in sarcoma growth by regulating cell motility, stemness, and angiogenesis. Endothelial cells and pericytes have been proposed as potential sources for activating Notch in osteosarcoma [38]. Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction and SIRT1 acts as an intrinsic negative modulator of Notch signaling in endothelial cells, which may be at the basis of the osteoclastogenesis vs. osteoblastogenesis in osteosarcoma [39, 40]. Crucially, it is widely considered that unregulated developmental processes have a significant impact on juvenile sarcomas. Currently, several published articles discuss the roles of epithelial and mesenchymal tissue markers in setting cell migrations in pediatric sarcoma. Preussner et al. examined the significance of epithelial/mesenchymal states regarding tumor cell plasticity in a hereditary rodent model (mouse) of rhabdomyosarcoma [41]. Within a genetically unstable and susceptible milieu of regenerated muscle, muscle stem cells triggered the formation of tumors through a process like the MET pathway, facilitated by the activation of zygotic Dux transcription factors. When Duxbl was excessively expressed in normal muscle stem cells during the experiment, it led to the expression of cadherin, the ability to become immortal, and the capability to develop tumors. The authors additionally established a connection between Dux transcription factors and the expression profiles of stem cells in malignancies originating from germ cells or epithelial cells supporting the existence of tumor heterogeneity and the identification of stem cell characteristics in rhabdomyosarcoma.

Dissemination models

The invasive characteristics of primary tumors may not necessarily indicate the ability to form distant metastases, which can lead to reduced overall survival. A recent study conducted by EpSSG revealed that tiny pulmonary nodules may be present in more than 20% of localized rhabdomyosarcoma cases at the time of diagnosis. However, it was not observed that these nodules impacted survival rates [42]. It is crucial to comprehend the factors that govern the proliferation of metastatic cells before, during, or after treatment, both locally and systemically, at various levels. The conventional linear progression model of metastasis is founded on the premise that genetic changes gradually accumulate inside the tumor, leading to the acquisition of metastatic characteristics by subclonal populations. The available evidence strongly supports an early and efficient spread of the phenomenon, together with the occurrence of concurrent advancements and colonization routes [43]. This approach aligns with the notion that the genetic changes occurring at metastatic sites can differ significantly from those observed in the parent tumor. Irrespective of the timing of dissemination in tumor progression, it also entails metastatic expansion in various anatomical sites particular to the type of tumor. The organotropic model of metastasis explains how the preference of certain tumor cells (seed) for specific organs (soil) enables successful metastasis. This model builds upon the traditional seed and soil theory but with modifications considering organ tropism’s role and pre-metastatic habitats [44].

On the other hand, the anatomical/mechanical model thinks of metastatic clones being filtered and flowing, with anatomical obstacles regulating their spread [44]. The extent to which each model contributes to different tumor types may be debatable. Still, it is evident that the presence of circulating tumor cells is a common occurrence, and the process of metastasis is widely regarded as inefficient [44]. The sarcoma tumor microenvironment exhibits significant variability based on subtype, anatomical location, age, gender, genetic complexity, and previous treatment. Various sources have recently examined a comprehensive analysis of the significance of vascular cells, immune cells, and immunotherapy in sarcoma [45, 46].

Extracellular matrix and its associated proteins

Weaver and other researchers have made persuasive contributions that have enhanced our fundamental comprehension of the significance of matrix stiffness and physical surroundings concerning tumor growth [47]. Sarcomas exhibit molecular results indicating that the physical (bio-mechanical) and chemical features of the TME synergistically contribute to the enhancement of sarcoma motility and metastasis through a feedback loop [48]. Nevertheless, ECM proteins frequently exert multiple effects in the TME and should be evaluated context-dependently concerning the specific organ and tissue involved. The TME consists of malignant, non-malignant stromal, vascular, and immune cells. Collagens, structural ECM proteins, and osteopontin, a matricellular protein, are crucial in providing both physical support and signaling cues essential for cell movements. Transforming growth factor-beta (TGFβ) regulates many proteins involved with the ECM, and these proteins have the potential to serve as biomarkers [49]. Sarcomas possess a distinctive characteristic where the differentiation between neoplastic cells and mesenchymal cells is remarkably ambiguous, primarily because of the stromal origin of the neoplastic cells. Cellular transdifferentiation of mesenchymal stem cells produced from bone marrow can also take place, and this process is recognized explicitly as significant in the advancement of osteosarcoma [22]. The presence of low oxygen levels in a TME usually promotes the growth of the tumor. The effects of varying oxygen levels within the tumor on the invasion of sarcoma cells have been investigated [50]. In humans, the EPAS1 gene is responsible for coding EPAS1 protein, an alias of which is HIF2alpha, an acronym for hypoxia-inducible factor 2 alpha. EPAS1 is a type of hypoxia-inducible factors, which are collected as a group of transcription factors involved in body response to oxygen level [51]. The vascular endothelial growth factor (VEGF) promoter, particularly in situations of hypoxia, is a downstream target of HIF-2 (other than HIF-1), and the expression levels of either HIF-1α or HIF-2α correlate positively to VEGF expression. In the future, there may be incitement to further evaluate protein–protein interaction and using experimental animal models [51]. HIF1α triggers the activation of the SDF1–CXCR4 signaling pathway in response to hypoxia [51]. Notably, the increased levels of the chemokine receptor CXCR4 remain present even when cells are exposed to normal oxygen levels again [52]. Sarcoma research has provided evidence that the SDF-1 ligand probably stimulates chemotaxis through membranes. This ligand may also act into the adherence to endothelial cells, and the production of matrix metalloproteinase 2 (MMP-2) [53]. There have been studies emphasizing that MMP-2 and MMP-9 may be considered prognostic indicators and are linked to the spread of cancer to other body parts in osteosarcoma [54–57]. The display of CXCR4 is seen in two-thirds of osteosarcomas and is associated with the expression of VEGF and reduced survival rates in patients [58, 59]. Rhabdomyosarcoma has also been associated with a link indicating reduced patient survival [60]. Currently, there are many tumor environments in which CXCR4-positive cancer cells are highly likely to spread to tissues that express SDF1 (CXCL12), such as the bone marrow [53]. The characteristic bone marrow milieu, containing both resident stem cells and progenitor cells, has a natural inclination to attract and sustain propagating tumor cells from many sources. Additional research confirms that the direct engagement or enlistment of mesenchymal stem cells originating from bone marrow enhances the growth and infiltration of the primary tumor [61]. One suggested way mesenchymal stem cells may function in the tumor microenvironment is by promoting stemness and resistance to chemotherapy through the NFκB pathway and release of IL6 [62]. Lysyl oxidases (LOX), which are recognized as potent regulators of structural alterations in healthy connective tissue, fibrotic conditions, and cancer, are critical in the process of tumor seeding [63]. The LOX family comprises catalytic enzymes that form cross-links between collagen and elastin within the tumor microenvironment. Multiple studies have now shown that LOX family members play an active role in the advancement of tumors and the spread of cancer to other parts of the body, regardless of the kind of tumor. Furthermore, there are documented accounts of tumor-suppressive effects, specifically in osteosarcoma [64]. The EWS-FLI oncoprotein in Ewing sarcoma decreases the expression of LOX, and the observed tumor-suppressive effects have been associated with a specific pro-peptide domain [65]. LOX and LOXL1 both possess pro-domains and undergo extracellular processing, distinguishing them from the family members, namely LOXL2, LOXL3, and LOXL4. Activating the mature protein necessitates the proteolytic elimination of its N-terminal LOX-propeptide, also known as LOX-PP. Thrombospondin-1 (TSP1) is a well-known glycoprotein found in the TME. It is mostly known for its ability to inhibit the formation of new blood vessels (anti-angiogenic) and its influence on the invasion of tumor cells. TSP1 achieves these effects by interacting with several molecules on the cell surface and matrix metalloproteinases [66, 67]. The α4β1 integrin has been associated with the pro-adhesive actions in osteosarcoma [68]. Since the approval of trabectedin for the treatment of advanced or metastatic soft-tissue sarcoma, various pharmacological mechanisms of action have been suggested, including anti-angiogenic effects on the cells of the endothelium and the elevation of TSP1 [69]. The study demonstrated that the TME produced higher levels of tissue inhibitor of metalloproteinases 1 and 2, leading to poor extracellular matrix remodeling. The extent to which TSP1 can function as a regulator of angiogenesis-dependent “dormancy” is yet unidentified.

Growth factors

Cell proliferation and differentiation in mesenchymal stem cells are frequently interconnected and controlled by growth factors such as TGFβ, platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) [70]. TGFβ is recognized as a crucial controller of the EMT phenomenon and the corresponding advancement of tumors in various types of cancer. High levels of TGFβ in osteosarcoma are associated with the grade of the tumor, resistance to chemotherapy, and the presence of metastases [68, 69]. Likewise, when the EMT transcription factors Snails, ZEBs, or Twist are excessively produced, it encourages the spreading of tumor cells [71]. Conversely, when the inhibitory transcription factor Smad7 is excessively produced or when illness development is prevented through pharmacological means, it hinders the advancement of the disease [72–76]. Nevertheless, genetic modifications and in vivo analyses also reveal the ability of TGFβ signaling in sarcoma to limit tumor growth [77]. TGFβ family members affect several cell types inside the TME. The TGFβ co-receptor endoglin is recognized as a marker for blood vessels in tumor biology. However, it is also seen in malignant cells and has been associated with tumor cell plasticity and poorer patient survival in Ewing sarcoma [78]. Additional factors involved in TGFβ-controlling angiogenesis include VEGF and connective tissue growth factor (CTGF) [79]. The appearance of VEGF has been linked to the density of blood vessels and a reduced period of disease-free survival in patients with osteosarcoma [80–82]. Recent studies have demonstrated that CTGF stimulates the formation of new blood vessels, enhances the production of MMP-2/3, and promotes the movement of cells in osteosarcoma. Conversely, reducing the levels of CTGF in an experimental mouse model decreased the spread of cancer to the lungs [81–84]. Additional research has demonstrated that CTGF can enhance osteosarcoma's resistance to drugs and control VEGF production from fibroblasts [85, 86]. The TGFβ pathway is also involved in the specific inhibition of the immunologic system [87, 88]. Osteosarcoma cells can control the recruitment and differentiation of infiltrating immune cells and build a localized immunologically tolerant milieu, hence facilitating tumor growth [89]. Additional experiments have demonstrated that the immune response in osteosarcoma can be reinstated by pairing an anti-TGFβ antibody with dendritic cells [90]. Gao et al. recently elucidated a novel method via which cancers evade detection by the innate immune system. They employed a model system of methylcholanthrene (MCA)-induced fibrosarcoma to investigate this phenomenon. The study proposed that tumor immunoevasion induced by TGFβ involved the transformation of anti-tumoral NK cells into type 1 innate lymphoid cells, resulting in the loss of their capacity to regulate local tumor growth and metastasis [91]. The PDGF pathway is a developmental signaling route that may be triggered during the formation of sarcomas. A recent study demonstrated that PDGF signaling maintains cancer stem cell characteristics, including self-renewal, tissue invasion, and resistance to chemotoxic therapy, in sarcoma [92, 93]. Increased levels of phosphorylated PDGFRα/β and EMT proteins were noted in spheroid cultures, which are enhanced for neoplastic stem cells. However, the migration and invasion were significantly reduced by up to 80% when treated with the tyrosine kinase inhibitor imatinib, which targets PDGFRα/β. Additionally, the expression of EMT proteins was also reduced. These findings align with previously documented oncogenic mechanisms of PDGF signaling, such as the self-stimulation of tumor cells, stimulation of surrounding mesenchymal cells of the stroma, promotion of blood vessel growth, and direction of tumor interstitial fluid pressure (IFP), which affects the movement of substances in and out of the tumor [94, 95]. Overall, the PDGF family is associated with initial tumor growth, metastasis, medication resistance, and unfavorable clinical outcomes in various types of cancers. However, the specific impact of PDGF activity on different subtypes of sarcoma is still not well understood [96]. PDGF receptor genetic abnormalities are found in around 2% of pediatric malignancies [6]. However, PDGF ligands and/or receptors are commonly found in osteosarcoma, PNET/Ewing sarcoma, and rhabdomyosarcoma, and there is a connection between their presence and the patient’s clinical fate [1, 5, 45, 96–99]. Notably, fusion genes such as PAX3–FOXO1 (found in alveolar rhabdomyosarcoma) and EWS-ETS (found in primitive neuroectodermal tumor or Ewing sarcoma) can intentionally trigger the expression of PDGF family members through experimental means [98, 99]. Significantly, the resistance mechanisms to treatment drugs in sarcoma have been found to include disrupted PDGF signaling. An illustrative instance of this phenomenon is the documented reciprocal influence between CXCR4 and PDGF signaling in Ewing sarcoma, wherein heightened CXCR4 expression is associated with metastasis and unfavorable patient prognosis [100, 101]. Upon administration of a CXCR4-targeting drug to tumor cells, activating PDGFRβ as a compensatory mechanism enhanced cell proliferation. However, applying a multi-kinase inhibitor, specifically dasatinib, effectively countered this effect. A recent study on rhabdomyosarcoma has discovered that the overexpression and constant activation of PDGFRα, along with its amplification, serve as a mechanism of acquired resistance to a drug that aims the insulin-like growth factor I receptor (IGF-IR) [102]. Collectively, these results emphasize the necessity of exploring the mechanisms by which anti-cancer drugs work to identify appropriate treatment combinations.

Most recent breaking update and future investigations

Metastasis is driven by a detailed and thorough cooperation between a neoplasm and its microenvironment, which results in the adaptation of molecular mechanisms that evade the immune system. It enables pre-metastatic niche formation. Roberts et al. studied the interferon regulatory factor 5 (IRF5) and found that its expression in osteosarcoma clinically correlates with prolonged survival and decreased secretion of tumor-derived extracellular vesicles (t-dEVs). The packaging of IRF5 mRNA in EVs caused downstream effects of decrease in the metastatic burden and an anti-tumorigenic microenvironment [103]. Phosphodiesterase 1B (PDE1B) has also been considered a potential biomarker associated with TME and clinical significance in osteosarcoma [104]. PDE1B high expression was related to a better tumor prognosis, suppressing immune escape from osteosarcoma [104]. Long noncoding RNA (lncRNA) is a non-coding RNA. LncRNAs have a length of more than 200 nucleotides and are involved in multiple regulatory processes in vivo, and pathology of several human diseases [105]. ROR1-AS1 is a cancer-associated lncRNA. This lncRNA is either over- or underexpressed in multiple malignancies, including colon carcinoma, hepatocellular carcinoma, and osteosarcoma among others [106, 107]. WNT5B (WNT Family Member 5B) expression has been identified as high in osteosarcoma stem cells [108]. It leads to increased stem cell proliferation and migration through the stemness gene SOX2 (SRY-box transcription factor 2).

Historically, the treatment of pediatric sarcomas has predominantly focused on chemotherapy. Different medicines have been employed, all of which share the characteristic of selectively killing malignant cells in both the primary tumor and any metastatic locations. We are transitioning into a new phase in the field of oncology, primarily defined using combination therapies and targeted treatments that specifically target cancerous cells and/or cells within the TME. Notable instances include the use of imatinib to treat dermatofibrosarcoma protuberans and gastrointestinal stromal tumors, as well as the use of pazopanib to treat metastatic non-adipocytic soft-tissue sarcoma [109]. Trabectedin, an alternative treatment for sarcoma, has received approval from the European Medicines Agency explicitly for curing soft-tissue sarcomas in adults. Trabectedin not only directly affects malignant cells but also alters the characteristics of tumor-associated macrophages. Muramyl tripeptide (mifamurtide) is a European Medicines Agency-approved therapeutic regimen targeting macrophages. It is utilized for the treatment of osteosarcoma. Immunotherapy is a new and promising approach to regulate the activity of immune cells in certain groups of patients. However, its use in sarcoma is still in the early stages of research. Investigations into the manipulation of the immune response in the microenvironment of pediatric sarcoma are also conducted through the utilization of tumor vaccines. The efficacy of such treatments is yet to be determined.

Conclusive remarks

Gaining a deeper comprehension of the activities occurring in the TME throughout pediatric sarcoma is crucial for enhancing patient prognosis and quality of life. Research on prevalent epithelial malignancies has been valuable in pinpointing potential molecular pathways implicated in the spread of cancer cells and resistance to treatment in sarcoma, specifically osteosarcoma (Fig. 1). Nevertheless, sarcomas possess a distinct mesenchymal origin, which sets them apart from epithelial tumors and necessitates a different approach when examining cellular processes such as EMT and MET. The diversity among different sarcoma subtypes, as well as within each subtype, poses significant difficulties. Therefore, applying discoveries from other contexts to pediatric sarcoma requires additional investigation.

Fig. 1 [Images not available. See PDF.]

Immune and non-immune components in the immune microenvironment of osteosarcoma and mechanisms of their pro-tumor/anti-tumor effects. CSF-1R colony-stimulating factor 1 receptor, PD-1 programmed cell death protein-1, EGFR epidermal growth factor receptor, IL interleukin, NETs neutrophil extracellular traps, ROS reactive oxygen species, NO nitric oxide, RANKL receptor activator NF-κB ligand, TGF-β transforming growth factor-beta, IFN-γ interferon-gamma, CXCL8 C-X-C motif chemokine ligand 8, AFP α-fetoprotein, HSP heat shock protein, TIM-3 T cell immunoglobulin and mucin domain-containing protein-3, OAA osteosarcoma-associated antigens, PD-L1 programmed cell death protein ligand-1, GRM4 glutamate metabotropic receptor 4, CCR7 chemokine receptor 7, TNF-α tumor necrosis factor-alpha, CTLA-4 cytotoxic T-lymphocyte-associated protein-4, BTLA B And T-lymphocyte attenuator, AIRE autoimmune regulator expression, hSFRP2 humanized secreted frizzled-related protein 2, TLR toll-like receptor, TAMs tumor-associated macrophages, TANs tumor-associated neutrophils, MDSCs myeloid-derived suppressor cells, MCs mast cells, MSCs mesenchymal stem cells, CTCs circulating tumor cells, C complement, DCs dendritic cells, NK cells natural killer cells

(Source: Zhu et al. [110])

Author contributions

CMS revised the literature and wrote the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

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