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Osteosarcoma - Using Animal Models To Learn More About Osteosarcoma

The prognosis for osteosarcoma, a malignancy that causes abnormal bone growth, is favorable.

Although osteosarcoma is the most frequent bone cancer, it accounts for fewer than 1% of all cancer cases in the US.

There is a second increase in the number of cases in adults over 60 after the first 10 years of life, while bones are still forming.

90% of pediatric and adolescent osteosarcomas begin in the intramedullary area of long bones in the lower extremities, typically in the metaphyses.

Loss of function in the affected extremity, local invasion of bone and soft tissue, and distant metastasis, most frequently to the lung, are the hallmarks of osteosarcoma (90 percent ).

Metastases can also develop in the bone (8–10%) and lymph nodes (occasionally). Treatment entails forceful excision of the primary tumor to enable local management through amputation or limb sparing surgery.

Osteoblastic, fibroblastic, and chondroblastic osteosarcoma are the three primary subtypes of the disease. Osteoblastic is the most prevalent kind, followed by chondroblastic and fibroblastic.

Symptoms Of Osteosarcoma

A common sign of osteosarcoma is pain in the affected bone, which is usually found around the knee or upper arm. The pain may worsen in the hours following a workout or at night. Osteosarcoma symptoms that you should be aware of include:

  • If the problem is in your legs, you will be unable to walk without limping.
  • An uncomfortable, heated mass under the skin that restricts movement if the problem is in the joints.
  • Even with minor movement, bones can fracture or break.
  • Movement of the legs which causes an increase in pain.
  • Increased agony when attempting to lift one's arms due to an unidentified fever.
  • An increase in the size and color of the tumor.

Causes And Risk Factors

While osteosarcoma has no established etiology, certain risk factors have been linked to an increased risk of the illness.

There is a gene mutation called RB1 that can cause osteosarcoma and hereditary retinal degeneration, a rare kind of eye cancer that affects youngsters, however the majority of instances are random.

Osteosarcoma is more likely to occur throughout adolescence when a youngster is experiencing rapid growth. There appears to be a correlation between bone expansion and tumor production, as demonstrated by this study.

Osteosarcoma is more likely to develop in the area that has been exposed to high doses of radiation, such as those used to treat other types of cancer. Tumors often take several years to develop after radiation treatment. In imaging procedures such as X-rays and CT scans, radiation dosages appear to be less harmful.

What Is The Etiology Of Osteosarcoma?

Genetic classification of osteosarcoma is difficult due to its complicated karyotype and lack of recurrent translocations. Many genes may be involved in the disease's development and spread.

Because of chromosomal abnormalities in osteosarcoma, it's hard to interpret these data. Li-Fraumeni and retinoblastic syndromes increase the risk of osteosarcoma. Half of all human osteosarcomas have somatic deletions or point mutations in P53, and half of these changes cause allele loss. 70% of osteosarcomas had RB allele mutations.

RB point mutations are more common than RB deletions. Several modifications affect the RB pathway. 22% of osteosarcomas had a dysfunctional INK4a/ARF locus or increased CDK4 gene expression. These changes suggest that osteosarcoma cell cycle checkpoints are often out of control.

Osteosarcoma biology requires more representative models. This is because osteosarcomas are aggressive and start early.

Types Of Animal Models In Osteosarcoma

Complex karyotype and no recurrent translocations characterize osteosarcoma. Genomic study has uncovered genes that may contribute to the disease's development and spread.

Osteosarcoma's genome has many chromosomal abnormalities, making interpretation difficult. Most osteosarcoma genetic mutations are random, however Li-Fraumeni and retinoblastoma syndromes increase risk. P53 is changed in 50% of all osteosarcoma patients, causing allele loss in unaffected people.

70% of osteosarcomas have a mutated RB allele. Only 6% of malignancies have RB point mutations, but 23% have RB deletions. RB pathway changes have also been found. ' 22% of osteosarcomas had amplified INK4a/ARF or CDK4 genes. Osteosarcoma frequently affects the G1/S and G2/M cell cycle checkpoints.

Animal models help better understand osteosarcoma biology. Due to its aggressiveness and unexpected origins, osteosarcoma is incurable.

Canine Models

Large dogs are more prone to osteosarcoma than people. This makes the dog a perfect illness model. Canine osteosarcoma is analogous to human malignancies in histology and gene expression. Age at onset and disease prevalence are major differences. In the U.S., 10,000 canines develop osteosarcoma each year.

This condition affects older, large-breed dogs (6–12 years). The typical disease-free period following surgery alone is four months; with chemotherapy, it's 13 months. This allows researchers to quickly imitate metastatic growth and progression and evaluate new treatment options. Canine osteosarcoma pathogenesis genes include P53, RB, and PTEN.

Although human and canine osteosarcoma models are similar, there are exceptions. Osteosarcoma is more common in older dogs than in teenagers. Some dog breeds have germ-line mutations that may affect osteosarcoma development and therapy.

Secondary Osteosarcoma After Radiation

Chemical and radioactive carcinogens exposed rats and mice to osteosarcoma models. In rats treated with P32-orthophosphate, osteosarcoma was common. Because of these models, researchers have produced human-like tumors and cell lines for osteosarcoma research. Because most osteosarcomas in humans are sporadic, therapy-induced diseases, the carcinogen-induced murine model better represents the human illness despite its high penetrance.

Xenotransplantation Studies

Development and application of human and murine osteosarcoma xenograft and allograft models in immunocompromised mice is extensively documented. The implanted cells become a solid tumor within days or weeks. These systems are common in oncological research due to their quick start, low cost, and ease of use and maintenance.

Donor-derived osteosarcoma cells may move to the lungs to study primary and secondary tumor progression. The use of fully developed osteosarcoma cells raises questions about the tumor's development. If the disease is introduced directly into a recipient animal, tumor-microenvironment interactions may be lost. So long as the implanted cell line isn't metastatic, it's hard to study rodent illness spread.

Many groups have utilized this model to reveal osteosarcoma migratory characteristics and screen tumoricidal drugs. The subcutaneous cell suspension injection model's high rate of occurrence and reproducibility enable for reliable titration of cell counts in the inoculum to determine tumorigenic potential. This design has benefits.

Transplanting patient-derived tumors into recipient animals is an alternative to injecting cell suspensions. Human malignant cells can grow in their native environment, maintaining the heterogeneity essential for their proliferation, which some research demonstrates enhances tumor growth and spread.

With cell suspensions and transplants, murine host cells can infiltrate the tumor, possibly impacting tumor cell activity. In rare situations, rodent host cells can outgrow human cells. Orthotopic intratibial OS cell implantation induces OS at local and metastatic locations (proximal tibia and lung).

This technique allows the investigation of original tumor formation in a more native milieu and early stages of OS metastatic progression, reconstituting the full metastatic process. Its usage is limited by the technical ability necessary to accomplish the implantation and the lack of quantified inoculum.

Genetically Engineered Mouse Models

Osteosarcoma is one of the best-studied sarcomas, as indicated by its many mouse models. Gene targeting technologies allow for the deletion or enhancement of mouse genes.

P53 and RB alterations in human osteosarcoma have been duplicated in animal models. When P53 was removed from the germ line, osteosarcoma incidence was 4% in homozygotes and 25% in heterozygotes, showing P53's role in osteosarcoma. This unusual tumor development ratio is presumably due to early death in the homozygous null population.

The rapid development of other malignancies (primarily lymphomas), the long latency of osteosarcoma, and the requirement to sacrifice mice before osteosarcoma start limit the value of these models. Using P53 knock-in mice with a mutant copy of P53R172H (similar to the R175H hot-spot mutation in humans), researchers demonstrated P53's relevance. Rb homologous deletion is embryonic lethal, and heterozygotes are not vulnerable to osteosarcoma, unlike mice with germ-line Rb deletions.

Conditional gene regulation and tissue-specific Cre expressing animal lines have greatly improved our ability to create specialized models of mesenchymal osteogenic lineage. Loss of P53 alone or in conjunction with Rb pathway disruption generates penetrant osteosarcoma models.

Conditional gene regulation and tissue-specific Cre-expressing mouse lines have substantially improved our ability to develop mesenchymal osteogenic lineage models that more closely match human OS. Most of these models generate penetrant OS by removing P53 with or without disrupting the Rb pathway. They apply conditional gene deletion on mesenchymal progenitors, pre-osteoblasts, and osteoblasts.

The Targeted Therapies In Osteosarcoma

Despite its unusual karyotype, osteosarcoma has been researched extensively in mice. Increased gene targeting technologies let scientists control gene expression.

Hereditary and sporadic human osteosarcoma P53 and RB mutations have been duplicated in mice models. Osteosarcoma incidence was 4% in homozygous P53 null mice and 25% in heterozygous P53 animals, showing that mutant P53 promotes osteosarcoma.

This unusual ratio of tumor growth is presumably due to the early death of homozygous nulls. Rapid development of other malignancies (primarily lymphomas), osteosarcoma's longer latency, and the requirement to sacrifice animals before osteosarcoma onset limit the usefulness of these models.

P53 is crucial when R175H hot-spot mutant P53-knock-in mice establish initial tumors and spread to other organs. Germ-line deletion of Rb prevented osteosarcoma in mice, however heterozygotes are not at risk for developing osteosarcoma.

By using conditional gene regulation and tissue-specific Cre expressing mouse lines, we may create models of mesenchymal osteogenic lineage that more closely reflect human osteosarcoma. Most osteosarcoma models are based on P53 loss with or without Rb pathway disruption.

Accurate determination of disease burden at inaccessible places is another preclinical testing consideration. In vivo imaging allows illness detection and monitoring. Many researchers can't afford expensive imaging devices.

OS is more accessible than abdominal malignancies since the underlying tumor in genetically altered mouse models is in long bones. Small micrometastases are difficult to monitor/visualize. Inaccurate preclinical appraisal of metastatic spread can lead to unsatisfactory clinical results.

There's a lot of interest in refining approaches for reproducible, ultrasensitive single-cell metastasis detection. Microcomputer tomography (micro-CT), positron emission tomography (PET), bioluminescence, or fluorescence imaging are used to detect tumor cells in vivo.

A woman holding her knee with both hands with the muscles and bone around the knee highlighted in red and blue
A woman holding her knee with both hands with the muscles and bone around the knee highlighted in red and blue

People Also Ask

What Are Osteosarcoma Symptoms?

Pain or tenderness in the bones is one of the most typical indications that a patient has osteosarcoma. A growth or lump (sometimes known as a tumor) that is warm to the touch and can be felt through the skin. inflammation and a bright red color at the site of your tumor.

Is Osteosarcoma A Death Sentence?

Osteosarcoma is characterized by a number of symptoms, the most prevalent of which are pain or tenderness in the bones. A tumor is a mass or lump that is warm and can be felt through the skin. There is redness and swelling at the location of your tumor.

Can Osteosarcoma Be Removed?

The vast majority of procedures for osteosarcoma can be performed in such a way as to remove all of the cancer while sparing the limb, which enables the patient's function to be preserved. The stage of the tumor and the amount of muscle and tissue that needs to be removed both play a role in determining whether or not this operation is a viable choice.

Does Osteosarcoma Run In Families?

There are several subtypes of osteosarcoma, the most common of which are osteoblastic, chondroblastic, and fibroblastic. Other subtypes include telangiectatic, multifocal, parosteal, and periosteal osteosarcoma. There is no clear understanding of what triggers osteosarcoma. There have been reports of it running in families, and at least one gene has been linked to an elevated risk of developing the condition.

Conclusion

When it comes to the biology of osteosarcoma, the absence of predisposition factors or precursor lesions makes it challenging for researchers to comprehend the illness. Human tissue has its limitations when it comes to research into the underlying mechanisms that drive the genesis of tumors, the progression of tumors, the occurrence of metastatic events, and therapeutic interventions.

This deficit is filled by animal models. The study of osteosarcoma animal models has revealed insights into the genesis and progression of tumors, in addition to the cellular and molecular profiles of tumors, despite the fact that these models do not have a completely realistic representation of the disease.

Gene knockout investigations have led to the discovery of genetic mutations that expedite the beginning of tumors (P53), as well as co-operative genetic mutations that raise the incidence of disease (RB, c-FOS).

When using cell lineage specific markers, it is now possible to investigate osteosarcoma incidence and tumor pathology by introducing genetic mutations sequentially from early precursor (multipotent mesenchymal cell) to more mature osteoblastic cells (osteoblast to osteocyte) cells.

This can be done by targeting genetic mutations sequentially from osteoblast to osteocyte cells. Following the conditional mutation of P53, this technique has been utilized to identify mesenchymal cells with Prx1 and osteoprogenitor cells with Osx. Both of these cell types are precursors to osteoblasts.

However, it is not yet clear whether these populations are actually separate from one another, given that Prx1 can be coexpressed with Osx in a certain subpopulation of cells.

About The Authors

Katharine Tate

Katharine Tate - I’m a native of Massachusetts, where I earned bachelor's degrees in Health, Science, Society, and Policy and Sculpture from Brandeis University. I enjoy assisting and inspiring women in all aspects of their lives, and I consider myself a partner in their OB an GYN treatment. I particularly enjoy forming relationships with young women and assisting them in determining their healthcare needs and goals. I love to travel, create metal and fiber art, cook, and spend time outside. Also, I’m fluent in both German and American Sign Language.

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