Therapeutic Potential Of Adult Bone Marrow-Derived Mesenchymal Stem Cells In Prostate Cancer Bone Metastasis

Main Category: Prostate / Prostate Cancer
Also Included In: Stem Cell Research;  Cancer / Oncology
Article Date: 17 Mar 2010 - 5:00 PDT


UroToday.com - Adult bone marrow-derived mesenchymal stem cells (MSC) have been shown to inhibit tumor growth in various studies. Although MSC express MHC class I molecules, they lack expression of co-stimulatory molecules and suppress T-cell response, which gives them the utility to overcome a wide range of immunologic barriers. Additionally the ability of MSCs to home in on the sites of tumor growth is well known as their plasticity allows them to differentiate into bone, cartilage, fat, muscle, neurons and other tissue types. Systemic administration of MSC in mice has been shown to engraft within the tumor microenvironment in many cancers and thus represents an attractive vehicle for cell gene therapy strategies.

In a preclinical mouse model, recently we have shown the application of unmodified MSC, constitutively expressing osteoprotegerin (OPG) in inhibiting the growth of prostate tumor in the bone by formation of new bone and prevention of bone loss. Although this treatment has shown potential at earlier stages of bone metastasis, it lacked significance when tested against established prostate tumors in the bone. This limitation was due to the number of MSC that could be injected into mice tibia; an excess of 5X105 cells routinely resulted in some degree of pulmonary embolism. In this scenario, the number of cancer cells in established tumors greatly outnumbered the MSC, hence resulting in modest therapeutic effects.

Apart from therapeutic advantages of the OPG expressing MSC in early stages of bone metastasis, the present study also indicated the presentation of woven bone in prostate cancer bone metastasis. In our study, the therapeutic effect of the MSC is initially imparted in woven bone formation surrounding the tumor nests. Formation of woven bone is normal in fracture healing and characteristic to osteoblastic metastasis in prostate cancer, unlike other bone metastatic cancers that are predominantly of osteolytic nature. Based on our observations, we hypothesized that woven bone formation in prostate cancer bone metastasis is an endogenous therapeutic response imparted by the resident MSC. Roudier and colleagues (2008) studied bone samples obtained from prostate cancer patients with bone metastasis and demonstrated that the woven bone formation in the osteoblastic metastases originated from the skeletal MSC, which also supports our findings. When we compared growth kinetics of highly osteolytic human prostate cancer cell line PC3 and osteoblastic C4-2B cell line in mouse tibiae, PC3 cells aggressively proliferated and resulted in severe bone loss within a month's time, whereas C4-2B cells grew at a significantly slower rate, initially generated an osteoblastic phenotype but in long-term turned to an osteolytic phenotype. We believe that the slow progression of C4-2B cells provides a therapeutic window for the endogenous MSC to restore bone lost due to the initial osteolytic event and required by the cancer to establish growth in the bone microenvironment. This observation needs to be confirmed in human patients with prostate cancer bone metastasis.

Our in vitro co-culture assay indicated MSC did not have any negative effect on the proliferation of the prostate cancer cell line PC3. In our animal model, MSC treatment restricted tumor growth in the bone but failed to abolish the tumor altogether. Therefore, therapeutic application of MSC alone may not be sufficient for the eradication of bone metastatic tumors. Ex vivo engineered MSC expressing tumoricidal genes, besides maintaining their self-renewal and differentiation properties, will be helpful as a combination therapy. MSC treatment can also be applied as an adjuvant therapy besides chemotherapy or radiation therapy to restore bone loss and to prevent cancer-promoting mechanisms such as angiogenesis.

This study was based on a localized tumor in the mouse tibia and does not accurately represent bone metastasis in prostate cancer that is widespread in the skeleton. Therefore, the suggested concept needs to be further tested in a total-body skeletal metastasis, in a preclinical animal model, before clinical translation to humans.

Written by Diptiman Chanda, PhD, and Selvarangan Ponnazhagan, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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