Primary Bone Tumors Research Articles

A Novel Defined Necroptosis-Related Genes Prognostic Signature for Predicting Prognosis and Treatment of Osteosarcoma.

Osteosarcoma (OS) is a frequent primary malignant bone tumor, with a poor prognosis. Necroptosis is strongly correlated with OS and may be an influential target for treating OS. This study's objective was to establish a necroptosis-related gene (NRG) prognostic signature that could predict OS prognosis and guide OS treatment. First, we identified 20 NRGs associated with OS survival based on the TARGET database. We then derived a 7 NRG prognostic signature. Our findings revealed that the 7 NRG prognostic signature performed well in predicting the survival of OS patients. We next analyzed differences in immunological status and immune cell infiltration. In addition, we examined the relationship between chemo/immunotherapeutic response and the 7-NRG prognostic signature. In addition, to probe the mechanisms underlying the NRG prognostic signature, we performed functional enrichment assays including GO and KEGG. Finally, CHMP4C was selected for functional experiments. Silencing CHMP4C prevented OS cells from proliferating, migrating, and invading. This 7-NRG prognostic signature seems to be an excellent predictor that can provide a fresh direction for OS treatment.

Soft tissue chondromyxoid fibroma.An extremely rare case

Chondromyxoid fibroma is a rare benign bone tumor that accounts for less than 1% of primary bone tumors. The soft tissue variant of this tumor is extremely rare. Herein, we present a case of soft-tissue chondromyxoid fibroma in the foot of a 13-year-old boy treated with surgical excision.

A novel CircRNA Circ_0001722 regulates proliferation and invasion of osteosarcoma cells through targeting miR-204-5p/RUNX2 axis

BackgroundOsteosarcoma (OS) is the most prevalent primary fatal bone neoplasm in adolescents and children owing to limited therapeutic methods. Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the roles of circRNAs in OS are still unclear.MethodsFirstly, we evaluate the differentially expressed circRNAs in 3 paired OS and corresponding adjacent nontumor tissue samples by circRNA microarray assay, finding a novel circRNA, circ_001722, significantly upregulated in OS tissues and cells. The circular structure of candidate circRNA was confirmed through Sanger sequencing, divergent primer PCR, and RNase R treatments. Proliferation of OS cells was evaluated in vitro and in vivo. The microRNA (miRNA) sponge mechanism of circRNAs was verified by dual-luciferase assay and RNA immunoprecipitation assay.ResultsA novel circRNA, circ_001722, is significantly upregulated in OS tissues and cells. Downregulation of circ_0001722 can suppress proliferation and invasion of human OS cells in vitro and in vivo. Computational algorithms predict miR-204-5p can bind with circ_0001722 and RUNX2 mRNA 3’UTR, which is verified by Dual-luciferase assay and RNA immunoprecipitation assay. Further functional experiments show that circ_0001722 competitively binds to miR-204-5p and prevents it to decrease the level of RUNX2, which upregulates proliferation and invasion of human OS cells.ConclusionCirc_001722 is a novel tumor promotor in OS, and promotes the progression of OS via miR-204-5p/RUNX2 axis.

Manoalide Induces Intrinsic Apoptosis by Oxidative Stress and Mitochondrial Dysfunction in Human Osteosarcoma Cells.

Osteosarcoma (OS) is the most common primary malignant bone tumor that produces immature osteoid. Metastatic OS has a poor prognosis with a death rate of >70%. Manoalide is a natural sesterterpenoid isolated from marine sponges. It is a phospholipase A2 inhibitor with anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to investigate the mechanism and effect of manoalide on OS cells. Our experiments showed that manoalide induced cytotoxicity in 143B and MG63 cells (human osteosarcoma). Treatment with manoalide at concentrations of 10, 20, and 40 µM for 24 and 48 h reduced MG63 cell viability to 45.13-4.40% (p < 0.01). Meanwhile, manoalide caused reactive oxygen species (ROS) overproduction and disrupted antioxidant proteins, activating the apoptotic proteins caspase-9/-3 and PARP (Poly (ADP-ribose) polymerase). Excessive levels of ROS in the mitochondria affected oxidative phosphorylation, ATP generation, and membrane potential (ΔΨm). Additionally, manoalide down-regulated mitochondrial fusion protein and up-regulated mitochondrial fission protein, resulting in mitochondrial fragmentation and impaired function. On the contrary, a pre-treatment with n-acetyl-l-cysteine ameliorated manoalide-induced apoptosis, ROS, and antioxidant proteins in OS cells. Overall, our findings show that manoalide induces oxidative stress, mitochondrial dysfunction, and apoptosis, causing the cell death of OS cells, showing potential as an innovative alternative treatment in human OS.

FAM60A promotes osteosarcoma development and progression.

Osteosarcoma (OS) is a highly malignant primary bone tumor. Family of homology 60A (FAM60A) reportedly contributes to the malignant growth of some tumors. Herein we investigated the mRNA expression level of FAM60A by combining OS and non-cancer samples from public databases. Immunohistochemistry was performed to determine protein expression levels of FAM60A in patients with OS. Further, RT-qPCR and western blotting were conducted to evaluate FAM60A expression in various OS cell lines. CCK-8 assay, colony formation assay, and flow cytometry were applied to determine the function of FAM60A. Finally, functional enrichment analysis was performed based on FAM60A co-expressed genes. FAM60A mRNA expression level was found to be significantly upregulated (standardized mean difference = 1.27, 95% CI [0.67-1.88]). Survival analyses suggested that higher expression of FAM60A was indicative of poor prognoses. Similarly, FAM60A protein expression level was also observed to be upregulated. Knocking down FAM60A expression inhibited OS cell proliferation, increased apoptosis, and blocked cells from entering the S phase. Besides, cell cycle was the most prominently enriched pathway, and BUB1, DTL, and EXO1 were identified as hub genes. FAM60A expression was found to be markedly upregulated in OS; furthermore, FAM60A was observed to promote OS cell proliferation, inhibit apoptosis, and participate in cell cycle regulation. Besides, FAM60A may interact with hub genes to participate in the progress of OS.

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis.

Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including p53, RB, and ATRX, and hyperactivation of the tumor promoter genes, including MYC and MDM2, in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future.

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies.

Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb-preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD-1/PD-L1, MAPK, and NF-κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway-based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.

MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag-MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape.

Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS. [89Zr]Zr-DFO-IF3 was injected into three healthy beagle dogs. PET/CT was conducted at 4, 24, 48, and 72 h. RAPID analysis was used to determine the dosimetry of [177Lu]Lu-CHXA"-IF3 for a clinical trial in companion dogs with OS. IF3 antibody was biotinylated, and a multitude of human tissues were assessed with immunohistochemistry. PET/CT revealed that only the liver, bone marrow, and adrenal glands had high uptake. Clearance was initially through renal and hepatobiliary excretion in the first 72 h followed by primarily physical decay. RAPID analysis showed bone marrow to be the dose-limiting organ with a therapeutic range for 177Lu calculated to be 0.487-0.583 GBq. Immunohistochemistry demonstrated the absence of IGF2R expression on the surface of healthy human cells, thus suggesting that radioimmunotherapy with [177Lu]Lu-CHXA"-IF3 will be well tolerated. Image-based dosimetry has defined a safe therapeutic range for canine clinical trials, while immunohistochemistry has suggested that the antibody will not cross-react with healthy human tissues.

The Eph/Ephrin system in primary bone tumor and bone cancer pain.

The family of Eph receptor tyrosine kinases and their Ephrin ligands system constitutes a bidirectional signaling pathway. Eph/Ephrin system coordinate a wide spectrum of pathologic processes during development, metastasis, prognosis, drug resistance and angiogenesis in carcinogenesis. Chemotherapy, surgery and radiotherapy are the most commonly used clinical treatments for primary bone tumors. Therefore, surgical resection is often unable to completely eliminate the tumor, and this is the main cause of metastasis and postoperative recurrence. A growing body of literature has been published lately revitalizing our scientific interest towards the role of Eph/Ephrins in pathogenesis and the treatment of bone tumor and bone cancer pain. This study mainly reviewed the roles of Eph/Ephrin system that has both tumor-suppressing and -promoting roles in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of Eph/Ephrin system in tumorigenesis and metastasis of bone tumors might provide a foundation for the development of Eph/Ephrin targeted anti-cancer therapy.

Schisandrin B Inhibits Osteosarcoma Cell Proliferation and Promotes Apoptosis Through PI3K/AKT/mTOR Pathway Mediated Autophagy

Osteosarcoma is the most common primary malignant bone tumor; the main treatment method is surgery and adjuvant chemotherapy, with a 5-year survival rate of less than 20% for metastatic patients. Schisandrin B is the most abundant and active ingredient found in the fruit of Schisandra chinensis (Turcz.) Baill., Schisandraceae, which has document properties such as liver protection, antioxidant, anti-inflammatory, antiaging, and antitumor. The present investigation explored the therapeutic effect of schisandrin B on osteosarcoma (MG63 cells). Cell proliferation and viability, scratch assay, and transwell migration analysis were used to detect the effects of schisandrin B on the growth activity, migration, and invasion of MG63 cells. The effects of schisandrin B on MG63 cell apoptosis were detected by flow cytometry and tunel staining. Western blot was used to detect the expression levels of autophagy and apoptosis related proteins. Immunofluorescence staining was used to detect schisandrin B effects of autophagy and apoptosis on MG63 cells. Schisandrin B inhibited the growth activity, migration ability, and invasion ability of osteosarcoma cells. In addition, schisandrin B induced apoptosis of MG63 cells through autophagy mediated by PI3K/AKT/mTOR signaling pathway.Graphical

The management and approach to osteosarcoma in children: A mini-review article

Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The onset of OS is associated with local pain and swelling as well as joint dysfunction, occasionally. The most common location for OS is around the knee joint. These patients often tend to receive medical attention following physical exercise and trauma. The affected population is mainly teenagers, children, and young adults with age range of 10-30 years.&#x0D; OS can be diagnosed via different approaches. The main serum markers for pediatric OS are insulin‑like growth factor (IGF‑1 and IGFBP‑3), anti‑ki57 antibody, tumor necrosis factor (TNF)‑β and sTNF‑R, T3, CD44, vascular endothelial growth factor, serum amyloid A, CXC chemokines, bone alkalin phosphatase, Interleukin (IL‑2, IL‑4, IL‑8), interferon gamma (IFN-γ), TNF‑α, and free polyamines.&#x0D; Given that there is no comprehensive review literature regarding OS management in our country, this study aimed to assess a survey on the management and approach of OS in children. In this regard, we have discussed the epidemiology, etiology, type, clinical feature, diagnosis, and OS therapy.

Features of routing, diagnosis and combined treatment of pathological fractures of long tubular bones of tumor etiology

Introduction. In the structure of fractures of long tubular bones, pathological fractures account for about 1 %, and 2/3 of all cases are pathological fractures associated with bone metastases. Primary bone tumors are complicated by the development of a pathological fracture in 1– 10 % of cases, bone metastases in 8–30 % of cases. With a pathological fracture, as the primary manifestation of the tumor process, as a rule, patients come to the attention of orthopedic traumatologists providing emergency care. In the practice of oncologists, there are often patients with bone tumors who have performed deliberately non-radical surgical interventions associated with insufficient oncological alertness of traumatologists.Aim. To study and present the results of combined treatment of patients with bone tumors complicated by a pathological fracture.Materials and methods. The results of treatment and observation of 159 patients with tumors of long tubular bones complicated by a pathological fracture or the threat of its development, who received combined or surgical treatment and were observed in the polyclinic of the Republican Oncological Dispensary from 2008 to 2020, were analyzed.Results. A pathological fracture that has taken place, in the absence of somatic contraindications, is not a contraindication to neoadjuvant treatment, which allows performing organ-preserving surgical treatment with optimal local and systemic control. However, with verified bone metastases, when segmental bone resections are not shown, and the diagnosis of myeloma (solitary plasmocytoma) is established, it is permissible to perform surgery in a trauma hospital, after consulting an oncologist.Conclusion. The combined approach in the treatment of malignant bone tumors complicated by a pathological fracture makes it possible to perform a functional-saving, organ-preserving surgical intervention, significantly reducing the risk of tumor recurrence and systemic progression.

Long-term Outcome of Total Femur Replacement.

Total femur replacement is an option instead of amputation for extensive bone tumour or after revision surgery with a massive bone loss. Over a long period of time the patients may need revision surgery, and this might affect the functional outcome. We reviewed all consecutive total femur replacements done for primary and revision surgery of primary bone tumours in our centre to evaluate the long-term functional outcome and survival. All patients who had total femur resection and reconstruction with modular endoprosthesis replacement in our centre from June 1997 to May 2022 were reviewed. The respondents were surveyed through WhatsApp using google form which was translated into Bahasa Malaysia based on the Musculoskeletal Tumour Society Scoring System (MSTS). The data were presented as descriptive data on the final survival of the limb and prosthesis. Ten patients underwent total femur replacement. There were eight osteosarcoma, one giant cell tumour and one chondromyxoid fibroma. Three patients with osteosarcoma succumbed to pulmonary metastases; all had good early post-operative functional outcomes without local recurrence. Seven patients were available for long term evaluation of function with a mean follow-up of 17.6 years (ranged 10-25 years). Four patients with total femur replacement had good functional outcomes (60-80%) without revision with 10-25 years follow-up. Three patients experienced acetabulum erosion and chronic pain that required early hip replacements. Two of them were complicated with superior erosions and bone loss and subsequently were managed with massive reconstruction using cemented acetabulum cage reconstruction. The other has diabetes mellitus with chronic infection following revision of distal femur endoprosthesis to total femur replacement and subsequently underwent limited hemipelvectomy after 14 years. Total femur replacement offers a good long term functional outcome and prosthesis survival and is a favourable option for limb salvage surgery.

Osteosarcoma as a GES-Listed Pathology: 7-Year Experience at a National Reference Center

Osteosarcoma (OS) is the most frequent malignant primary bone tumor. The explicit health guarantee (GES) plan in Chile, a law that guarantees diagnosis, treatment, and rehabilitation, incorporated OS in 2014. To describe the characteristics of the population over 15 years, with a histopathological diagnosis of OS, to define survival rate and complications, and to identify variables that affect these outcomes. A retrospective study from 2014 to 2020, including all patients affiliated with the public health system diagnosed with OS, with histological confirmation. From clinical records, we extracted demographic data, anatomical OS location, histopathological findings, admission stage, presence of metastases, treatment, complications, and survival. We determined prognostic factors by multivariate analysis. 133 patients, 58.8% men, the average age was 31 years, and the most frequent location was the distal femur (34.9%). 56.4% of the patients were admitted in Enneking stage IIB, and 36.4% presented metastasis at admission. 14.3% presented complications, the most frequent periprosthetic infection (6 cases). 16% of patients evolved with local recurrence. The multivariate model showed that age and metastases at admission constitute independent prognostic variables, with a hazard ratio of 1.017 for age (p = 0.016) and 3.13 for metastases (p = 0.0000). In the subgroup analysis, patients without metastases at diagnosis had a 5-year survival of 54% versus 11% for the group with metastases. Adjusting for age, the 5-year survival for the non-metastatic and metastatic groups was 73% and 22%, respectively. This is our country's first demographic description study of patients with OS. In our series, the age of presentation and the presence of metastases at admission were factors that significantly affect prognosis. When adjusting for age, the survival percentages are comparable to those reported in other international centers specialized in sarcomas.

MiRNA-520a-3p combined with folic acid conjugated Fe2O3@PDA multifunctional nanoagents for MR imagine and antitumor gene-photothermal therapy

Osteosarcoma (OS) is a primary malignant bone tumor that occurs mainly in adolescents. Researchers are devoting to develop combination therapy methods in a multifunctional nanoplatform for the treatment of osteosarcoma. The results of previous research have shown that up-regulation of miR-520a-3p could induce anticancer effects in osteosarcoma. In order to improve the effect of gene therapy (GT), we attempted to carry miR-520a-3p in a multifunctional vector for comprehensive therapy. Fe2O3 is a type of magnetic resonance imaging (MRI) contrast that is widely used as a drug delivery agent. When coated with polydopamine (PDA), it can also be used as a photothermal therapy (PTT) agent (Fe2O3@ PDA). To deliver nanoagents targeted to a tumor site, folic acid (FA) conjugated with Fe2O3 @PDA was manufactured as FA-Fe2O3@PDA. FA was chosen as the target molecule to enhance utilization and reduce toxicity of nanoparticles. However, the therapeutic efficacy of FA-Fe2O3-PDA combined with miR-520a-3p has not yet been studied. In this study, we synthesized FA-Fe2O3@PDA-miRNA and investigated the potential of combining PDA regulated PTT and miR-520a-3p regulated GT to kill osteosarcoma cells. The results indicated that down-regulation of interleukin 6 receptor (IL6R) by miR-520a-3p and the photothermal ability of PDA could induce satisfactory anticancer effects in osteosarcoma, and the curative ratio was better than that used alone PTT or GT. Moreover, as a kind of T 2 magnetic contrast, miRNA-Fe2O3@PDA-FA can be used for MRI. These findings indicated that miRNA-Fe2O3@PDA-FA is an effective anti-tumor nanovector for PTT combined with GT.

A rare presentation site for osteochondroma scapula and pelvis, intramembranous ossifying bones of axial skeleton: case series

Osteochondroma is the most common primary bone tumour comprising over 33% of benign bone tumours. The formation of osteochondroma occurs because of exophytic protuberance on the surface of growing bones. The most common sites for osteochondroma are the distal femur, proximal tibia, and proximal humerus. We are presenting a case series of three patients with rare presentation sites of osteochondroma, scapula and pelvis. Osteochondroma is primarily disease of appendicular skeleton but we are reporting it in axial skeleton. Radiographic findings include fluffy cartilaginous outgrowth arising from the external surface of a long tubular bone that may be pedunculated or sessile. Osteochondromas usually develop in bones that develop by enchondral ossification and rarely develop in bones developing by intramembranous ossification like pelvis. These tumours are usually asymptomatic but can cause pubic visceral compression or neurovascular compromise by compressing external and internal iliac vessels and lumbosacral pluxes. Scapular osteochondroma can cause compression or neurovascular compromise in thoracic cavity and axillary vessels and brachial pluxes. Treatment with surgical excision gives consistent results and relief of pain.

Bisphosphonate treatment as a safe choice for treating lung metastases of recurrent giant cell tumor of bone

Giant cell tumor (GCT) accounts for 5% of all primary bone tumors and 20% of benign skeletal tumors. This case report presents the case of a 17-year-old female with a recurrent giant cell tumor and lung metastases. The patient received bisphosphonate therapy instead of surgery. The use of zoledronic acid for lung metastases from GCT may have conservatively improved clinical symptoms and radiological assessments can be achieved.

SERUM VITAMIN D IN PATIENTS WITH BENIGN, PRIMARY MALIGNANT AND METASTATIC BONE TUMORS

Participant in the process of normal bone remodeling is vitamin D, which, in addition, has antiinflammatory (anti-cytokine), anti-proliferative and anti-tumor effects. Objective of the study is to assess the level of 25-hydroxyvitamin D3 concentration in blood serum before the start of treatment in patients with benign, primary malignant and metastatic bone tumors, taking into account polymorbidity. Materials and methods. The following patients were included in the study: 21 patients with benign pelvic bone tumors; 52 patients with malignant tumors of the bones of the pelvis and lower limbs; 52 patients with metastatic tumors of the bones of the pelvis and lower limbs. The control group consisted of 22 practically healthy volunteers without chronic diseases. The content of vitamin D was determined by the immunochemiluminescence method. The results. The content of vitamin D in blood serum in patients with benign bone tumors is in the range from 22.4 to 29.6 ng/ml, with primary malignant tumors — from 7.8 to 15.9 ng/ml, with metastatic ones — from 13.8 to 15.5 ng/ml. There are no statistically significant differences between the histotypes of primary malignant bone tumors (p &gt; 0.05). Conclusions. Polymorbidity statistically significantly increases vitamin D deficiency in patients with osteogenic sarcoma and patients with metastatic bone tumors (p &lt; 0.05). According to the national classification of vitamin D content, patients with benign bone tumors have a suboptimal level of vitamin D, while patients with primary malignant and metastatic bone tumors have vitamin D deficiency.

Cancer-associated fibroblast infiltration in osteosarcoma: the discrepancy in subtypes pathways and immunosuppression.

Introduction: Osteosarcoma (OS), the primary malignant bone tumor, has a low survival rate for recurrent patients. Latest reports indicated that cancer-associated fibroblasts (CAFs) were the main component of tumor microenvironment, and would generate a variable role in the progression of tumors. However, the role of CAFs is still few known in osteosarcoma. Methods: The processed RNA-seq data and the corresponding clinical and molecular information were retrieved from the Cancer Genome Atlas Program (TCGA) database and processed data of tumor tissue was obtained from Gene Expression Omnibus (GEO) database. Xcell method was used in data processing, and Gene set variation analysis (GSVA) was used to calculates enrichment scores. Nomogram was constructed to evaluate prognostic power of the predictive model. And the construction of risk scores and assessment of prognostic predictive were based on the LASSO model. Results: This study classified Cancer Genome Atlas (TCGA) cohort into high and low CAFs infiltrate phenotype with different CAFs infiltration enrichment scores. Then TOP 9 genes were screened as prognostic signatures among 2,488 differentially expressed genes between the two groups. Key prognostic molecules were CGREF1, CORT and RHBDL2 and the risk score formula is: Risk-score = CGREF1*0.004 + CORT*0.004 + RHBDL2*0.002. The signatures were validated to be independent prognostic factors to predict tumor prognosis with single-factor COX and multi-factor COX regression analyses and Norton chart. The risk score expression of risk score model genes could predict the drug resistance, and significant differences could be found between the high and low scoring groups for 17-AAG, AZD6244, PD-0325901 and Sorafenib. Discussion: To sum up, this article validated the prediction role of CAF infiltration in the prognosis of OS, which might shed light on the treatment of OS.