Bone Metastasis: Experimental and Clinical Therapeutics

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However, metastatic tumors to the mandibular bone are not a rare phenomenon. Many cases with metatastic breast carcinoma to the mandible have been reported and their metastases are well documented.

Current status and future directions in the treatment of bone metastases from breast cancer

Metastases in the oral region can occur in oral soft tissues or the mandibular bone. Metastatic tumors in the mandibular bone are more frequently reported than those in the oral mucosa. Primary sites are usually the breast, lung, intestine, ovaries, prostate, thyroid, kidney, testes, uterine cervix, and adrenal glands 9 , 11 , 12 , 14 , 15 , 17 , 19 , 23 , 24 , 27 , 30 - Many authors reported that breast cancer metastasis to the oral cavity is more frequent for a disseminated tumor to involve the mandible rather than the maxilla 1 , Hormone therapy and sterilization may often result in the conversion of osteolytic lesions to the osteoblastic type 2.

Taken together, breast carcinoma has a great tendency to be spread by metastasis, thus it is a common clinical problem associated with bone destruction and a poorer prognosis.

Impact of Bone Metastases on the Skeleton

Breast carcinoma metastasizes to the mandibles three times as often as any other malignant tumor Also it has been reported that periodontal diseases are associated with breast cancer Therefore, a metastasis of an aggressive breast cancer to the mandible has a tendency to increase. However, the complete understanding is lacking about the process how breast cancer metastasizes to the mandibles with the most frequency at the cellular level.

Consequently, diversified insights into the molecular mechanism of breast cancer metastasis to the mandible are necessary to devise preventive and therapeutic approaches. An appropriate animal model might have an additional advantage to understand the mechanisms underlying the metastatic process and to test the effects of potential lead compounds.

Due to the technical complication, there is a low success rate in most trials due to the susceptibility of bacterial contamination and the weak cellular activity of primary tumors as opposed to metastatic tumors 7 , Human tumor xenografts using the orthotopic transplantation of histologically intact tissues of several carcinomas have not been adopted for a metastatic animal model although these models represent the entire environment that occurs during cancer progression Thus, xenograft models have been used to study the development and metastasis of human carcinomas.

SPARC inhibits breast cancer bone metastasis and may be a clinical therapeutic target

The xenograft animal model with a cultured cancer cell line is technically simple and reflects more precisely the morphology and character of their respective original tumor. Nevertheless, there is no single animal model that precisely replicates all of the events and circumstances that occur during cancer progression. The most widely used model for cancer development and behavior research is the flank model. However, not all transplanted cancer cells develop tumors at an atopic site due to the different cancer environments and no spontaneous metastasis does occur 4. Also in case of a mammary fat pad xenograft, breast cancer development has shown a low success rate in most trials due to the technically limited occurrence of mammary glands in neonatal mice.

Also, an intra-tibia inoculation of breast cancer is frequently applied as a cancer-bone metastasis model. In this model, cancer cells are inserted extra-capsulary through the tibial crest, epiphysis, and growth plate and then cells are sequentially injected into the bone marrow space.

The intra-tibia model does not precisely reflect the characteristics of bone-invasive OSCC 8 , Thus, it fails to address certain aspects of the clinical situation. This model is not suitable to elucidate the cellular and molecular mechanisms of metastatic breast cancer to mandible and could not serve as suitable tool in the development of new therapeutic agents against metastatic breast cancer to bone. MDA-MB cell is triple-negative and preferentially metastasizes to the bone 5. Particularly, metastatic MDA-MB breast cancer cells have a clinical tendency to be spread to mandible.

In many types of animal models including tibia, MDA-MB cells led to osteolytic bone destruction, reproducibly. However, a complete understanding of how breast cancer metastasizes to the mandibles with the most frequency at the cellular level is lacking. Above all, in this study, we tried to find a proper animal model of metastatic breast cancer to the mandibular bone. Experimental metastases refer to the injection of tumor cells directly to the systemic circulation. Metastatic breast cancer cells have a great tendency to be spread to bone including mandible. Therefore, research groups have been adopting the intracardiac injection method for osteolytic metastasis model 17 , 18 , 25 , Although this animal model accurately reflects the bone disease portion of the clinical disease, the complete mechanism of how breast cancer metastasizes to the mandibles with the most frequency at the cellular level is not clear.

The a ctive hematopoietic tissue is known as red bone marrow. Bones with red marrow are the favored sites for metastatic deposits Mainly in elderly persons, jawbones have little active marrow, while remnants of hematopoietic active marrow are detected in the posterior areas of the mandible and the hematopoietically active sites attract metastatic tumor cells. Meanwhile, the oral soft tissues have a rich network of capillaries which can entrap malignant cells.

Bone Metastasis | Gurmit Singh | Springer

Proliferating capillaries display an uneven basement membrane, thereby increasing the penetration of tumor cells. In addition, inflammation plays an aggravative role in attracting metastatic cells to the gingiva 9. Osteolytic lesions were widely observed in both cancellous and cortical bones. The subsequent histological evaluation of tissue sections from the mandible confirmed the spontaneous tumor metastasis.

In animal models, bioluminescent imaging is a useful and sensitive method for detection of primary cancer growth and for tracking the metastasis in animal models 6 , In addition, luciferase-expressing cells permit the real-time tracking of tumor sites in living animals. The development of breast cancer to mandible mouse model remains a challenge in the preclinical evaluation of therapies for human breast cancer.

Now, the current xenograft model serves as suitable research tool and this application offers the preclinical assessment of anticancer therapies in vivo.


Metastatic breast cancer of the oral cavity. Am J Otolaryngol. Breast ductal carcinoma metastasis to jaw bones: a case report. Novel Biomed. Platelet and osteoclast beta3 integrins are critical for bone metastasis. The last decade has witnessed impressive progress in the field of immunotherapy. Recent evidence of robust clinical responses has been seen in multiple malignancies, including metastatic melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma RCCs , breast cancer, and hematological malignancies Partly, the reason behind this success is the capacity of these interventions to suppress tolerance to tumor antigens.

The immunotherapeutic approaches available now include cancer vaccines, checkpoint inhibitors, oncolytic viruses, and adoptive T-cell or NK cell transfer. Here, we will focus on immune checkpoint inhibitors because they fit more closely the paradigm of restoring immunological homeostasis in the tumor microenvironment. It is well-known that tumor cells have developed efficient mechanisms to escape immune recognition. These include tolerance induction, immune evasion, and interference with T cell signaling.

Upregulation of PD-L1 on tumor cells leads to engagement of PD-1 on T lymphocytes and suppression of the cytotoxic immune response even in the presence of proper recognition of tumor antigen by the TCR. A thorough review on this subject can be found in Alsaab et al. More recently, testing in clinical trials was initiated for the treatment of non-small cell lung carcinoma NSCLC , small cell lung cancer, bladder cancer, and metastatic hormone-refractory prostate cancer.

In addition, response to ipilimumab may take several months to manifest, making it difficult to assess therapeutic efficacy , These include pembrolizumab previously named as lambrolizumab; anti-PD1 and nivolumab anti-PD1 A lot of the excitement over therapy with checkpoint inhibitors rests on the robust therapeutic responses seen in some patients with these agents. In clinical trials for melanoma, nivolumab was associated with often durable clinical responses A case report is presented in Figure 6. The study illustrates successful therapy with nivolumab in a patient with metastatic mucosal melanoma who ultimately achieved a durable complete response Figure 6.

Clinical evidence that treatment with the immune checkpoint inhibitor, nivolumab is effective against metastatic mucosal melanoma. Systemic clinical response to nivolumab treatment. Computed tomography images from baseline May , 2 months into treatment and approximately 2 years later. Yellow arrows or circles indicate metastatic foci and their complete disappearance by March The green arrow depicts the level of LDH at the selected time points. LDH lactate dehydrogenase.

Reprinted from Ascierto et al. The anti-PD-L1 antibody atezolizumab has shown promise in a wide range of malignancies, including colon, lung, renal cell, gastric, head and neck cancer, and melanoma. Clinical approval has been obtained for pembrolizumab and nivolumab for melanoma and NSCLC, whereas nivolumab has also been approved for RCC and metastatic urothelial carcinoma [reviewed in Farkona et al. In addition to the robust durable therapeutic responses that have been achieved with PDPD-L1 inhibitors, these agents have also displayed a manageable toxicity profile.

Unlike CTLA-4 inhibitors, PD-1 inhibitors are associated with mild immunostimulation that can be treated with supportive care and steroid administration Taken together, these observations suggest that metastatic cancer could be managed successfully by restoring homeostasis in the immunological microenvironment of the tumor cell. A successful approach for treating metastasis would invariably include intervention at the level of the metastatic cell. One unique property of metastatic tumor cells that could be targeted for therapy is their resistance to anoikis.

Anoikis is a type of programmed cell death, which occurs when anchorage-dependent cells detach from the ECM.

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Healthy cells usually stay associated with the tissue to which they belong since their survival depends critically on communication between proximal cells and the ECM. When these cells are detached from the ECM, they invariably undergo anoikis. By contrast, metastatic tumor cells can become resistant to anoikis. This capability is key to their escape from the primary tumor, survival in the lymphatics or circulation, and ultimately, colonization of other vital organs 12 , — Based on this knowledge, it becomes clear that by restoring sensitivity to anoikis in metastatic tumor cells, one could trigger programmed cell death in these cells in a way that is efficient and spares healthy cells.

In our search for a therapeutic target that fits this profile, we focused on microRNAb as a key initiator of metastasis and driver of resistance to anoikis. In a seminal study, Ma et al. In patients, miRb has been implicated in metastasis and disease outcome of multiple malignancies including lung, breast, gastric, colorectal, bladder, ovarian, pancreatic, hepatocellular, and brain cancer, to name a few — In our own studies, we identified miRNAb as a master regulator of the viability of metastatic tumor cells.

We determined that miRb not only promotes the capacity of tumor cells to migrate and invade surrounding tissue become metastatic but also serves as a powerful master regulator of the viability of these cells — Detailed mechanistic studies confirmed the existence of a miRb-triggered pathway that regulates the viability and proliferation of tumor cells only after they have acquired the ability metastasize, pointing to miRb as a driver of resistance to anoikis This knowledge allowed us to develop a therapeutic strategy based on miRb inhibition.

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The specific inhibition of miRb was achieved using inhibitory oligonucleotides LNA-based antagomirs delivered to metastatic sites by dextran-coated iron oxide nanoparticles termed MN-anti-miR10b. We demonstrated that MN-anti-miR10b could completely prevent the formation of de novo metastases and, when combined with low-dose chemotherapy, caused complete and persistent regression of local lymph node metastasis in a murine breast cancer model Figure 7 Figure 7.

Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics
Bone Metastasis: Experimental and Clinical Therapeutics Bone Metastasis: Experimental and Clinical Therapeutics

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