Osteosarcoma pathophysiology: Difference between revisions

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* [[Parathyroid hormone-related protein|PTHrP]] leads to chemoresistance by downregulated expression of proapoptotic [[Bax (biochemistry)|Bax]] and PUMA and upregulated anti-[[Apoptosis|apoptotic]] [[Bcl-2]] and Bcl-xl and by blocking signaling via the p53, death-receptor and [[mitochondrial]] pathways of [[apoptosis]].  
* [[Parathyroid hormone-related protein|PTHrP]] leads to chemoresistance by downregulated expression of proapoptotic [[Bax (biochemistry)|Bax]] and PUMA and upregulated anti-[[Apoptosis|apoptotic]] [[Bcl-2]] and Bcl-xl and by blocking signaling via the p53, death-receptor and [[mitochondrial]] pathways of [[apoptosis]].  


=== Chromosomal Abnormalities <ref name="pmid28494505">{{cite journal |vauthors=Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, von Luettichau I, Bielack S, O'Leary VB, Leib-Mösch C, Frishman D, Nathrath M |title=Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma |journal=Int. J. Cancer |volume=141 |issue=4 |pages=816–828 |date=August 2017 |pmid=28494505 |doi=10.1002/ijc.30778 |url=}}</ref><ref name="pmid28489060">{{cite journal |vauthors=Liu G, Wang H, Zhang F, Tian Y, Tian Z, Cai Z, Lim D, Feng Z |title=The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats |journal=Int J Mol Sci |volume=18 |issue=5 |pages= |date=May 2017 |pmid=28489060 |pmc=5454939 |doi=10.3390/ijms18051027 |url=}}</ref><ref name="pmid26626558">{{cite journal |vauthors=Bishop MW, Janeway KA, Gorlick R |title=Future directions in the treatment of osteosarcoma |journal=Curr. Opin. Pediatr. |volume=28 |issue=1 |pages=26–33 |date=February 2016 |pmid=26626558 |pmc=4761449 |doi=10.1097/MOP.0000000000000298 |url=}}</ref><ref name="pmid24631100">{{cite journal |vauthors=Regueiro García A, Saborido Fiaño R, González Calvete L, Vázquez Donsión M, Couselo Sánchez JM, Fernández Sanmartín M |title=[Osteosarcoma and ATR-16 syndrome: association or coincidence?] |language=Spanish; Castilian |journal=An Pediatr (Barc) |volume=82 |issue=1 |pages=e189–91 |date=January 2015 |pmid=24631100 |doi=10.1016/j.anpedi.2014.02.008 |url=}}</ref><ref name="pmid25551557">{{cite journal |vauthors=Both J, Krijgsman O, Bras J, Schaap GR, Baas F, Ylstra B, Hulsebos TJ |title=Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma |journal=PLoS ONE |volume=9 |issue=12 |pages=e115835 |date=2014 |pmid=25551557 |pmc=4281204 |doi=10.1371/journal.pone.0115835 |url=}}</ref>===
=== Chromosomal Abnormalities ===


* A various amount of [[chromosomal]] and [[Genetics|genetic]] syndromes are known to be linked to the [[osteosarcoma]] [[pathophysiology]].  
* A various amount of [[chromosomal]] and [[Genetics|genetic]] syndromes are known to be linked to the [[osteosarcoma]] [[pathophysiology]].<ref name="pmid28494505">{{cite journal |vauthors=Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, von Luettichau I, Bielack S, O'Leary VB, Leib-Mösch C, Frishman D, Nathrath M |title=Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma |journal=Int. J. Cancer |volume=141 |issue=4 |pages=816–828 |date=August 2017 |pmid=28494505 |doi=10.1002/ijc.30778 |url=}}</ref><ref name="pmid28489060">{{cite journal |vauthors=Liu G, Wang H, Zhang F, Tian Y, Tian Z, Cai Z, Lim D, Feng Z |title=The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats |journal=Int J Mol Sci |volume=18 |issue=5 |pages= |date=May 2017 |pmid=28489060 |pmc=5454939 |doi=10.3390/ijms18051027 |url=}}</ref><ref name="pmid26626558">{{cite journal |vauthors=Bishop MW, Janeway KA, Gorlick R |title=Future directions in the treatment of osteosarcoma |journal=Curr. Opin. Pediatr. |volume=28 |issue=1 |pages=26–33 |date=February 2016 |pmid=26626558 |pmc=4761449 |doi=10.1097/MOP.0000000000000298 |url=}}</ref><ref name="pmid24631100">{{cite journal |vauthors=Regueiro García A, Saborido Fiaño R, González Calvete L, Vázquez Donsión M, Couselo Sánchez JM, Fernández Sanmartín M |title=[Osteosarcoma and ATR-16 syndrome: association or coincidence?] |language=Spanish; Castilian |journal=An Pediatr (Barc) |volume=82 |issue=1 |pages=e189–91 |date=January 2015 |pmid=24631100 |doi=10.1016/j.anpedi.2014.02.008 |url=}}</ref><ref name="pmid25551557">{{cite journal |vauthors=Both J, Krijgsman O, Bras J, Schaap GR, Baas F, Ylstra B, Hulsebos TJ |title=Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma |journal=PLoS ONE |volume=9 |issue=12 |pages=e115835 |date=2014 |pmid=25551557 |pmc=4281204 |doi=10.1371/journal.pone.0115835 |url=}}</ref>
* Specific chromosomal abnormalities are known to be associated with [[osteosarcoma]] include: loss of [[chromosome 9]], [[chromosome 10]], [[chromosome 13]], and [[chromosome 17]] as well as gain of [[chromosome 1]].  
* Specific chromosomal abnormalities are known to be associated with [[osteosarcoma]] include: loss of [[chromosome 9]], [[chromosome 10]], [[chromosome 13]], and [[chromosome 17]] as well as gain of [[chromosome 1]].  
* Meanwhile, a recent studies demonstrated that the [[Amplification|amplifications]] of [[Chromosome 6|chromosome 6p21]], chromosome 8q24, and chromosome 12q14, as well as [[loss of heterozygosity]] of 10q21.1, are the most common genomic alterations in [[osteosarcoma]]
* Meanwhile, a recent studies demonstrated that the [[Amplification|amplifications]] of [[Chromosome 6|chromosome 6p21]], chromosome 8q24, and chromosome 12q14, as well as [[loss of heterozygosity]] of 10q21.1, are the most common genomic alterations in [[osteosarcoma]]

Revision as of 17:57, 12 October 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

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Overview

The main cause of osteosarcoma is not well-known, yet. However, a number of risk factors have been identified in this regard. Osteosarcoma can involve any bone but it usually affects the extremities of long bones near metaphyseal growth plates. The most common sites include

  • Femur 42% of cases ( the distal femur had around 75% of involvement).
  • Tibia 19% of cases ( the proximal tibia had around 80% of involvement).
  • Humerus 10% of cases ( the proximal humerus had around 90% of involvement).
  • Skull and jaw 8% of cases.
  • Pelvis 8% of cases.

Pathophysiology

Growth Factors

TGF-β

IGF

  • IGF-I and IGF-II are growth factors usually overexpressed by osteosarcomas.
  • IGF families bind corresponding receptors such as IGF-1R, causing the activation of the PI3K and MAPK transduction pathways.
  • Consequently they supports the cell proliferation and inhibition of apoptosis. Meanwhile, the Lentivirus-mediated snRNA targeting IGF-R1 increases the chemosensitivity and the anti-tumor response of osteosarcoma cells to docetaxel and cisplatin.

CTGF

Parathyroid hormone (PTH)

Chromosomal Abnormalities

Genetics

Genes involved in the pathogenesis of osteosarcomas include:

Transcription Factors [16][17][18][19]

Transcription is the process of forming single-stranded messenger RNA (mRNA) sequences in cell from double-stranded DNA. Transcription factors simplify binding of promoter sequences for specific genes to initiate the process. The transcription is usually tightly regulated and the deregulation may leads to the malignancies like osteosarcoma.

Activator protein 1 complex (AP-1)

It is a regulator of transcription. AP-1 is comprised of Fos (products of the c-fos) and Jun proteins (c-jun proto-oncogenes). AP-1 controls cell proliferation, differentiation, and also bone metabolism. Fos and Jun are found to be upregulated in high-grade osteosarcomas than the low-grade and benign osteosarcoma.

Myc

It is a transcription factor that acts in the nucleus to stimulate both cell growth and division process. Myc amplification has been causes the occurrence and the resistance to chemotherapeutic in osteosarcoma pathogenesis. Also, the down-regulation of Myc increased the therapeutic activity of methotrexate against the osteosarcoma cell.

Cell Adhesion and Migration [20][21][22][23]

Osteosarcoma is a highly metastatic tumor, and pulmonary metatases and known as the common cause of death. The metastatic sequence involves the detachment of osteosarcoma cells from the primary tumor, adhesion to the extracellular matrix, local migration and invasion through stromal tissue, intravasation, and extravasation. The ability of osteosarcoma cells to metastasise by such a pathway completely depended on the complex cell-cell and cell-matrix interactions.

Osteoclast Function [24][25][26][27]

Osteosarcoma invasion of bone relies on interactions between the bone matrix, osteosarcoma cells, osteoblasts, and osteoclasts. In response to the hypoxic and acidotic conditions the osteosarcoma cells release molecules such as: endothelin-1 (ET-1), VEGF, and PDGF . These factors have predominantly osteoblast-stimulatory functions. The PTHrP as an important GF and the IL-11 also act on osteoblasts ienhancing the expression of receptor activator of nuclear factor κB ligand (RANKL). RANKL is a key mediator of osteoclast differentiation and activity. The activated osteoclasts release proteases to resorb the nonmineralised components of bone. Consequently, the Osteoclast pathways (differentiation, maturation, and activation) have potential as therapeutic effect. For example: inhibition of bone resorption at the tumor-bone interface reduces the osteosarcoma local invasion

Bone Growth and Tumorigenesis [28][29][30][31][32][33][34][35][36][37][38]

Previous studies have revealed a positive significant correlation between the osteosarcoma development and the rapid bone growth occurs during puberty. Accordingly the peak age of osteosarcoma development is slightly earlier for female population. And patients affected by the disease are taller compared to the normal population of the same age group. Also, the epiphyseal growth plates of the distal femur and proximal tibia are known to be responsible for the increase in height that occurs during puberty. Meanwhile, the Paget’s disease which is a disorder characterized by both excessive bone formation and breakdown leads to a higher incidence of osteosarcoma among the affected individuals.

Environmental Factors known as carcinogens for osteosarcoma include:

  1. Physical agents
  2. Chemical agents
  3. Biological agents

Physical agents

- Meanwhile, the ionising radiation, implicated in only 2% of cases of osteosarcoma, has the best established roll in this regard. Meanwhile, the radiotherapy treatment in children develop a secondary neoplasm, and of these are sarcomas in 5.4% and 25% of cases, respectively.

Chemical agents

The chemical agents responsible for the osteosarcoma formation include:

  • methylcholanthrene
  • chromium salts
  • beryllium oxide
  • zinc beryllium silicate
  • asbestos
  • aniline dyes

Biological agents

Resent investigations suggested a viral origin for osteosarcoma which later got some controversies in this regard. It was stemmed from the detection of simian virus 40 (SV40) in osteosarcoma cells but later it was proposed that may in fact be due to laboratory contamination by plasmids containing SV40 sequences.

Tumor Suppressor Gene Dysfunction [39][40][41]

Any type of exposure to previously-mentioned environmental insults causes a significant damages on the somatic DNA. Due to the tumor-suppressor mechanisms this DNA damage necessarily may not lead to malignant cell line process. These tumor-suppressor mechanisms include:

Repair the DNA damage [42][43][44][45][12][46][47]

Apoptosis

The p53 and retinoblastoma (Rb) genes are the well-known tumor-suppressor genes in cellular system. However, sometimes these tumor suppressor genes may themselves become mutated causing the loss of their protective function effects. Its been reported that the mutations in both the p53 and Rb genes have been proven to be involved in osteosarcoma pathogenesis.

DNA damage → phosphorylate p53 → dissociation from Mdm2

P53 :

The p53 gene mutation found in 50% and 22% all cancers and osteosarcomas respectively. The expression of p53 positively reduced metastatic disease and improved survival for these patients. it is unclear whether p53 mutation or loss may affect tumor behavior. But, using the p53-null SaOS-2 osteosarcoma cell line showed that the adenoviral-mediated gene transfer of wild-type p53 reduced the cell viability and also increased the sensitivity to chemotherapeutic agents in affected cells. for example: Li-Fraumeni syndrome is characterized by an autosomal dominant mutation of p53 leading to the development of multiple cancers such as osteosarcoma.

Retinoblastoma

The Rb gene is critical to cell-cycle control. Inherited mutation of the Rb gene lead to the retinoblastoma syndrome which predisposes a patient to multiple malignancies such as osteosarcoma. The Rb protein controls the cell cycle by binding the transcription factor E2F. E2F usually is held inactive by Rb until the CDK4/cyclin D complex phosphorylates Rb. Mutations of Rb allow for the continuous cycling of cells thus leads to the osteosarcoma occurance. It should be noted that both germ-line and somatic mutations of Rb increases the risk of osteosarcoma.

Tumor Angiogenesis [48][49][50][51]

Tumour angiogenesis is essential for sustained osteosarcoma growth and metastasis. The most common sites for osteosarcoma spread include: Metastasis to the lungs and bone also relies on the formation and maintenance of blood vessels. A hypoxic and acidotic microenvironment exists at the proliferated osteosarcoma area. While the osteosarcoma is a relatively vascular tumor. Angiogenesis is regulated by the balance between pro-angiogenic and antiangiogenic factors. Antiangiogenic proteins such as thrombospondin 1, TGF-β, troponin I, pigment epithelial-derived factor (PEDF), and reversion-inducing cysteine rich protein with Kazal motifs (RECK) are downregulated in osteosarcoma.

Tumor Invasion [20][52][53][17]

Invasion of the surrounding tissues by osteosarcoma also involves degradation of the extracellular matrix using the Matrix metalloproteinases (MMPs).

MMPs are a family of zinc-dependent endopeptidases that are involved in a range of physiological processes including inflammation, wound healing, embryogenesis, and fracture healing. In normal healthy tissues, MMPs are regulated by natural inhibitors such as tissue inhibitors of MMPs (TIMPs), RECK, and α2 macroglobulin. but in the malignancis such as osteosarcoma, the MMPs break down extracellular collagens, facilitating both tumor and endothelial cell invasion. The urokinase plasminogen activator (uPA) system an other osteosarcoma invasion regulator interacting with MMPs. Accordingly, the downregulation of uPAR in an in vivo osteosarcoma model resulted in reduced primary tumor growth and fewer metastases.

Osteosarcoma Cell Proliferation, Apoptosis, and Anchorage-Independent Growth [54][55][56][57]

Malignant cells such as osteosarcoma cells are mostly resistant to apoptosis.Apoptosis consists of initiation phase and execution phase. Both intrinsic and extrinsic pathways regulate the initiation phase. The intrinsic pathway relies on increased mitochondrial permeability while extrinsic pathway is known as a death receptor-initiated pathway. Osteosarcoma cells are resistant to anoikis and proliferate despite deranged cell-cell and cell-matrix attachments. This resistance to anoikis called anchorage-independent growth (AIG).

References

  1. ↑ Kim HJ, Chalmers PN, Morris CD (February 2010). "Pediatric osteogenic sarcoma". Curr. Opin. Pediatr. 22 (1): 61–6. doi:10.1097/MOP.0b013e328334581f. PMID 19915470.
  2. ↑ Moore DD, Luu HH (2014). "Osteosarcoma". Cancer Treat. Res. 162: 65–92. doi:10.1007/978-3-319-07323-1_4. PMID 25070231.
  3. ↑ Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M (March 2010). "Clinical presentation and imaging of bone and soft-tissue sarcomas". Cleve Clin J Med. 77 Suppl 1: S2–7. doi:10.3949/ccjm.77.s1.01. PMID 20179183.
  4. ↑ Wu PK, Chen WM, Lee OK, Chen CF, Huang CK, Chen TH (November 2010). "The prognosis for patients with osteosarcoma who have received prior manipulative therapy". J Bone Joint Surg Br. 92 (11): 1580–5. doi:10.1302/0301-620X.92B11.24706. PMID 21037356.
  5. ↑ Obiedat H, Alrabadi N, Sultan E, Al Shatti M, Zihlif M (July 2018). "The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients". BMC Med. Genet. 19 (1): 112. doi:10.1186/s12881-018-0627-4. PMC 6035436. PMID 29980176.
  6. ↑ Sergi C, Shen F, Liu SM (2019). "Insulin/IGF-1R, SIRT1, and FOXOs Pathways-An Intriguing Interaction Platform for Bone and Osteosarcoma". Front Endocrinol (Lausanne). 10: 93. doi:10.3389/fendo.2019.00093. PMC 6405434. PMID 30881341.
  7. ↑ Colombo M, Platonova N, Giannandrea D, Palano MT, Basile A, Chiaramonte R (2019). "Re-establishing Apoptosis Competence in Bone Associated Cancers via Communicative Reprogramming Induced Through Notch Signaling Inhibition". Front Pharmacol. 10: 145. doi:10.3389/fphar.2019.00145. PMC 6400837. PMID 30873026.
  8. ↑ Weinman MA, Fischer JA, Jacobs DC, Goodall CP, Bracha S, Chappell PE (February 2019). "Autocrine production of reproductive axis neuropeptides affects proliferation of canine osteosarcoma in vitro". BMC Cancer. 19 (1): 158. doi:10.1186/s12885-019-5363-4. PMC 6379937. PMID 30777054.
  9. ↑ Haralambiev L, Wien L, Gelbrich N, Kramer A, Mustea A, Burchardt M, Ekkernkamp A, Stope MB, Gümbel D (January 2019). "Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells". Anticancer Res. 39 (1): 151–157. doi:10.21873/anticanres.13091. PMID 30591452.
  10. ↑ Boulay G, Volorio A, Iyer S, Broye LC, Stamenkovic I, Riggi N, Rivera MN (August 2018). "Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies". Genes Dev. 32 (15–16): 1008–1019. doi:10.1101/gad.315192.118. PMC 6075149. PMID 30042132.
  11. ↑ Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, von Luettichau I, Bielack S, O'Leary VB, Leib-Mösch C, Frishman D, Nathrath M (August 2017). "Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma". Int. J. Cancer. 141 (4): 816–828. doi:10.1002/ijc.30778. PMID 28494505.
  12. ↑ 12.0 12.1 Liu G, Wang H, Zhang F, Tian Y, Tian Z, Cai Z, Lim D, Feng Z (May 2017). "The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats". Int J Mol Sci. 18 (5). doi:10.3390/ijms18051027. PMC 5454939. PMID 28489060.
  13. ↑ Bishop MW, Janeway KA, Gorlick R (February 2016). "Future directions in the treatment of osteosarcoma". Curr. Opin. Pediatr. 28 (1): 26–33. doi:10.1097/MOP.0000000000000298. PMC 4761449. PMID 26626558.
  14. ↑ Regueiro García A, Saborido Fiaño R, González Calvete L, Vázquez Donsión M, Couselo Sánchez JM, Fernández Sanmartín M (January 2015). "[Osteosarcoma and ATR-16 syndrome: association or coincidence?]". An Pediatr (Barc) (in Spanish; Castilian). 82 (1): e189–91. doi:10.1016/j.anpedi.2014.02.008. PMID 24631100.
  15. ↑ Both J, Krijgsman O, Bras J, Schaap GR, Baas F, Ylstra B, Hulsebos TJ (2014). "Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma". PLoS ONE. 9 (12): e115835. doi:10.1371/journal.pone.0115835. PMC 4281204. PMID 25551557.
  16. ↑ Jiang Z, Zhang W, Chen Z, Shao J, Chen L, Wang Z (June 2017). "Transcription Factor 21 (TCF21) rs12190287 Polymorphism is Associated with Osteosarcoma Risk and Outcomes in East Chinese Population". Med. Sci. Monit. 23: 3185–3191. PMC 5503230. PMID 28663539.
  17. ↑ 17.0 17.1 Zhou Z, Li Y, Jia Q, Wang Z, Wang X, Hu J, Xiao J (August 2017). "Heat shock transcription factor 1 promotes the proliferation, migration and invasion of osteosarcoma cells". Cell Prolif. 50 (4). doi:10.1111/cpr.12346. PMID 28370690.
  18. ↑ Heng L, Jia Z, Bai J, Zhang K, Zhu Y, Ma J, Zhang J, Duan H (May 2017). "Molecular characterization of metastatic osteosarcoma: Differentially expressed genes, transcription factors and microRNAs". Mol Med Rep. 15 (5): 2829–2836. doi:10.3892/mmr.2017.6286. PMID 28260111.
  19. ↑ Ma C, Han J, Dong D, Wang N (June 2018). "MicroRNA-152 Suppresses Human Osteosarcoma Cell Proliferation and Invasion by Targeting E2F Transcription Factor 3". Oncol. Res. 26 (5): 765–773. doi:10.3727/096504017X15021536183535. PMID 28810933.
  20. ↑ 20.0 20.1 Lan H, Hong W, Fan P, Qian D, Zhu J, Bai B (2017). "Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells". Cell. Physiol. Biochem. 43 (2): 553–567. doi:10.1159/000480528. PMID 28965117.
  21. ↑ Tome Y, Kimura H, Kiyuna T, Sugimoto N, Tsuchiya H, Kanaya F, Bouvet M, Hoffman RM (July 2016). "Disintegrin targeting of an αvβ3 integrin-over-expressing high-metastatic human osteosarcoma with echistatin inhibits cell proliferation, migration, invasion and adhesion in vitro". Oncotarget. 7 (29): 46315–46320. doi:10.18632/oncotarget.10111. PMC 5216800. PMID 27331872.
  22. ↑ Park GB, Kim DJ, Kim YS, Lee HK, Kim CW, Hur DY (January 2015). "Silencing of galectin-3 represses osteosarcoma cell migration and invasion through inhibition of FAK/Src/Lyn activation and β-catenin expression and increases susceptibility to chemotherapeutic agents". Int. J. Oncol. 46 (1): 185–94. doi:10.3892/ijo.2014.2721. PMID 25339127.
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  24. ↑ Kelleher FC, O'Sullivan H (September 2017). "Monocytes, Macrophages, and Osteoclasts in Osteosarcoma". J Adolesc Young Adult Oncol. 6 (3): 396–405. doi:10.1089/jayao.2016.0078. PMID 28263668.
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  28. ↑ Jiang F, Zhang D, Li G, Wang X (March 2017). "Knockdown of DDX46 Inhibits the Invasion and Tumorigenesis in Osteosarcoma Cells". Oncol. Res. 25 (3): 417–425. doi:10.3727/096504016X14747253292210. PMID 27697093.
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  30. ↑ Yang L, Xie F, Li S (August 2017). "Downregulation of Homeobox B7 Inhibits the Tumorigenesis and Progression of Osteosarcoma". Oncol. Res. 25 (7): 1089–1095. doi:10.3727/096504016X14784668796788. PMID 27983923.
  31. ↑ Wang H, Xing D, Ren D, Feng W, Chen Y, Zhao Z, Xiao Z, Peng Z (October 2017). "MicroRNA‑643 regulates the expression of ZEB1 and inhibits tumorigenesis in osteosarcoma". Mol Med Rep. 16 (4): 5157–5164. doi:10.3892/mmr.2017.7273. PMC 5647050. PMID 28849077.
  32. ↑ Gill J, Connolly P, Roth M, Chung SH, Zhang W, Piperdi S, Hoang B, Yang R, Guzik H, Morris J, Gorlick R, Geller DS (2017). "The effect of bone morphogenetic protein-2 on osteosarcoma metastasis". PLoS ONE. 12 (3): e0173322. doi:10.1371/journal.pone.0173322. PMID 28264040.
  33. ↑ Brown HK, Tellez-Gabriel M, Heymann D (February 2017). "Cancer stem cells in osteosarcoma". Cancer Lett. 386: 189–195. doi:10.1016/j.canlet.2016.11.019. PMID 27894960.
  34. ↑ Zhang XH, Zhang Y, Xie WP, Sun DS, Zhang YK, Hao YK, Tan GQ (2017). "Expression and significance of calreticulin in human osteosarcoma". Cancer Biomark. 18 (4): 405–411. doi:10.3233/CBM-160266. PMID 28106543.
  35. ↑ Cortini M, Avnet S, Baldini N (October 2017). "Mesenchymal stroma: Role in osteosarcoma progression". Cancer Lett. 405: 90–99. doi:10.1016/j.canlet.2017.07.024. PMID 28774797.
  36. ↑ Liu K, Ren T, Huang Y, Sun K, Bao X, Wang S, Zheng B, Guo W (August 2017). "Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma". Cell Death Dis. 8 (8): e3015. doi:10.1038/cddis.2017.422. PMC 5596600. PMID 28837148.
  37. ↑ Jiang ZH, Peng J, Yang HL, Fu XL, Wang JZ, Liu L, Jiang JN, Tan YF, Ge ZJ (May 2017). "Upregulation and biological function of transmembrane protein 119 in osteosarcoma". Exp. Mol. Med. 49 (5): e329. doi:10.1038/emm.2017.41. PMC 5454443. PMID 28496199.
  38. ↑ Wycislo KL, Fan TM (2015). "The immunotherapy of canine osteosarcoma: a historical and systematic review". J. Vet. Intern. Med. 29 (3): 759–69. doi:10.1111/jvim.12603. PMC 4895426. PMID 25929293.
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  52. ↑ Zheng B, Ren T, Huang Y, Guo W (January 2018). "Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3". Biochem. Biophys. Res. Commun. 495 (2): 1695–1701. doi:10.1016/j.bbrc.2017.12.032. PMID 29225166.
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  57. ↑ Foley JM, Scholten DJ, Monks NR, Cherba D, Monsma DJ, Davidson P, Dylewski D, Dykema K, Winn ME, Steensma MR (April 2015). "Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling". J Transl Med. 13: 110. doi:10.1186/s12967-015-0466-4. PMC 4419490. PMID 25889105.

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