Osteosarcoma pathophysiology: Difference between revisions
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=== Osteosarcoma Cell Proliferation, Apoptosis, and Anchorage-Independent Growth === | === Osteosarcoma Cell Proliferation, Apoptosis, and Anchorage-Independent Growth === | ||
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). | 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== | ==References== | ||
Revision as of 17:41, 1 April 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 poximal humerus had around 90% of involvement).
- Skull and jaw 8% of cases.
- Pelvis 8% of cases.
On gross pathology, areas of bone formation, hemorrhage, fibrosis, and cystic degeneration on cut surface are characteristic findings of osteosarcoma. On microscopic histopathological analysis, presence of osteoid within the tumor, pleomorphic cells, anaplastic cells, and atypical mitoses are characteristic findings of osteosarcoma. Osteosarcoma may be associated with hereditary syndromes such as Li-Fraumeni syndrome and Rothmund-Thomson Syndrome.
Pathophysiology
Traditionally, our knowledge about osteosarcoma has been mostly anatomical but it should be noted that it arises most commonly in the metaphyseal region of long bones, within the medullary cavity, then it involves the bone cortex; consequently a pseudocapsule forms around the penetrating tumor. Osteosarcoma is characterised as a highly cellular tumour consisted of: pleomorphic spindle-shaped cells responsible for the producing an osteoid matrix. However, recent developments in the field of medical sciences and the molecular biology have provided huge insights regarding the molecular pathogenesis of osteosarcoma:
Growth Factors
Impaired expression of growth factors leads to the accelerated proliferation of cells. Most important growth factor include:
- Transforming growth factor (TGF)
- Insulin-like growth factor (IGF)
- Connective tissue growth factor (CTGF)
- Parathyroid hormone (PTH)
TGF-β
These proteins are a large family of dimeric proteins and they influence a wide variety of cell process such as differentiation, proliferation, apoptosis, and matrix production. Bone morphogenic proteins (BMPs) build a large component of the TGF-β families. Expression of the TGF-β1 is significantly higher in High-grade osteosarcomas. Resent studies revealed an association between increased susceptibility and metastasis of osteosarcoma with TGFR1 variants, TGFBR1*6A, and Int7G24A.
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 shRNA targeting IGF-R1 increases the chemosensitivity and the antitumour response of osteosarcoma cells to docetaxel and cisplatin.
CTGF
CTGF related to a number of proteins in the CCN family (CTGF/Cyr61/Cef10/NOVH). Like TGF-β which was mentioned before the CTGF has a diverse range of functions including adhesion, migration, proliferation, survival, angiogenesis, and differentiation. CTGF act through the integrin signalling pathways.
Parathyroid hormone (PTH)
Parathyroid hormone (PTH), and its related peptide (PTHrP) and receptor (PTHR1) play important rolls in the progression and metastasis of osteosarcoma. PTHrP associated with tumour metastasis and hypercalcaemia. PTHrP leads to chemoresistance by downregulated expression of proapoptotic Bax and PUMA and upregulated antiapoptotic Bcl-2 and Bcl-xl and by blocking signalling via the p53, death-receptor and mitochondrial pathways of apoptosis.
Chromosomal Abnormalities
A various amount of chromosomal and genetic syndromes are known to be linked to the osteosarcoma pathophysiology. Specific chromosomal abnormalities are known to be associated with osteosarcoma include: loss of chromosomes 9, 10, 13, and 17 as well as gain of chromosome 1. Meanwhile, a recent studies demonstrated that the amplifications of chromosomes 6p21, 8q24, and 12q14, as well as loss of heterozygosity of 10q21.1, are the most common genomic alterations in osteosarcoma; It should be noted that patients carrying these alleles had a poorer prognosis. Meanwhile, Osteosarcoma had been reported in patients with the below mentioned genetic disorders:
- Bloom syndrome: characterised by genetic defects in the RecQ helicase family
- Rothmund-Thompson syndrome: characterised by genetic defects in the RecQ helicase family
- Werner syndrome: characterised by genetic defects in the RecQ helicase family
- Li-Fraumeni syndrome
- hereditary retinoblastoma.
*DNA-helicases are responsible for the double-stranded DNA prior to replication separation process. Mutations in these genes increases a higher risk of multiple malignancies.
Transcription Factors
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 the 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
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
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
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 characterised by both excessive bone formation and breakdown leads to a higher incidence of osteosarcoma among the affected individuals.
Environmental Factors
Environmental Factors known as carcinogens for osteosarcoma include:
- Physical agents
- Chemical agents
- 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
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
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
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
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 tumour growth and fewer metastases.
Osteosarcoma Cell Proliferation, Apoptosis, and Anchorage-Independent Growth
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).