Cell Transplantation, Vol. 24, pp. 625–630, 2015 Printed in the USA. All rights reserved. Copyright Ó 2015 Cognizant Comm. Corp.
0963-6897/15 $90.00 + .00 DOI: http://dx.doi.org/10.3727/096368914X685096 E-ISSN 1555-3892 www.cognizantcommunication.com
Review Bone Marrow-Derived Stem Cell Therapy for Metastatic Brain Cancers Yuji Kaneko,* Naoki Tajiri,* Meaghan Staples,* Stephanny Reyes,* Diego Lozano,* Paul R. Sanberg,* Thomas B. Freeman,* Harry van Loveren,* Seung U. Kim,† and Cesar V. Borlongan* *Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA †Department of Neurology, University of British Columbia, Vancouver, Canada
We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood–brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumorderived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases. Key words: Brain tumor; Stem cells; Transplantation; Gene therapy
INTRODUCTION To date, there is scarcity of evidence on treatment strategies targeting blood–brain barrier (BBB) repair in metastatic brain cancers. Metastatic cancers are among the most common mass lesions in the brain, with estimated 98,000~170,000 annual cases in the US, equating to approximately 24~45% of all cancer patients and accounting for 20% of cancer deaths each year (13,31,37,40,46). A transiently deteriorated BBB function allows systemic diseases to be seeded into the central nervous system (CNS) (14,15,19), leaving the brain a safe haven for tumor growth (3,29). Interruption of the BBB permeability permits entrance of inflammationassociated molecules into the CNS. Repair of the BBB function could attenuate the influx of inflammationassociated molecules, ultimately diminishing the subsequent protumorigenic effects.
Melanoma is a cancer of the skin that can manifest into a more serious form of skin cancer because it can metastatize to other body parts (e.g., brain) and can result in increased morbidity and mortality. Accordingly, the transition of melanoma into metastatic brain tumor provides an opportunity for understanding the basic scientific mechanism of tumor formation, but also opens avenues for developing new treatments, such as stem cell therapy, for brain cancer. Moreover, because half a million Americans are diagnosed yearly with melanoma, treatment of melanoma-induced metastatic brain tumor is a significant unmet clinical need. To this end, we advance the concept of stem cell therapy for treating melanoma. The overarching hypothesis of this study is that BBB breakdown accompanies brain metastatic cancers of melanoma and allows inflammatory factors from systemic circulation to penetrate the BBB, increasing the malignancy
Received May 8, 2014; final acceptance September 20, 2014. Online prepub date: October 10, 2014. Address correspondence to Professor Cesar V. Borlongan, Ph.D., Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Tel: +1-813-974-3154; Fax: +1-813-974-3078; E-mail:
[email protected]
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Figure 1. (A) Brain metastatic cancers of melanoma at an acute stage. (B, upper figure) A delayed stage of metastasis characterized by tumor enlargement and accompanied by BBB damage and CNS entry of deleterious inflammatory factors from the systemic circulation. Treatment with antitumor medications can reduce tumor growth (middle figure in B), but may only render transient benefits, with brain metastasis resuming its malignancy due to continuous brain penetration of harmful inflammatory factors via the leaky BBB (lower figure in B). (C) The potential of stem cell therapy as standalone treatment or as an adjunct to antitumor medications to repair the BBB and prevent systemic inflammation from exacerbating brain metastatic cancers.
of such metastatic brain cancers. Recognizing this leaky BBB-mediated inflammation as exacerbating, we next hypothesize that stem cell therapy will repair the BBB via angiogenesis, suppressing brain inflammation and ultimately reducing brain tumor growth and malignancy. We postulate that stem cell transplantation will repair the BBB and reduce brain inflammation, thereby abrogating brain metastasis of melanoma. This review article will offer new insights into the benefits of cell therapy. There are still concerns regarding the use of stem cells to treat any cancer; of note, transplanted cells could support angiogenesis or vasculogenesis that lends itself to tumor growth, provide trophic support for tumors, or the stem cells themselves could become cancerous. To date, there
is a paucity of data on treatment strategies targeting BBB repair in brain cancers. In fact, the notion of angiogenesis or vasculogenesis is frowned upon as this cell proliferative process is thought to exacerbate formation of metastatic cancers. Here we propose a paradigm-shifting approach, whereby we will initially show that the continued neglect of decreased angiogenesis and vasculogenesis accompanies BBB destruction, thereby contributing to the pathological formation of brain metastatic cancers of melanoma. Subsequently, we will demonstrate that bone marrow-derived endothelial progenitor cell therapy can augment angiogenesis and vasculogenesis, resulting in repair of the BBB and thereafter attenuation of developing brain metastatic cancers. This proposed study as
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advanced in this review article thus represents a significant advance over published data on the pathology and therapy for brain cancers. Targeted stem cell-driven vasculogenesis and angiogenesis could serve to repair the BBB dysfunction resulting from tumor metastasis into the brain. The notion of angiogenesis/vasculogenesis is often discredited as this is assumed to exacerbate formation of metastatic cancers. Like every other cell in the human body, proliferation and metastasis of cancer cells depend on vasculature for nutrients, oxygen, and the removal of wastes. As tumors expand, so does their metabolic demand and need for vasculature. This increased vasculature is achieved through angiogenesis (12,17) interacting with neurovascular units (45). The resulting expanded vasculature serves to support the rapidly increasing metabolic demands of the tumor, facilitating tumor expansion and increasing the likelihood of metastasis (42). For this reason, numerous recent studies have focused on antiangiogenic treatments of tumors (5). Tumor-associated vasculature, however, is commonly poorly structured and functionally impaired due to the rapid rate of growth by which it is developed. These vessels are not under the normal physiological circumstances to support the needs of the dependent tissue and can lead to hypoxia and low pH within the surrounding environment (21,22,33). Inhibiting angiogenic and vasculogenic activity contributes to the detrimental microenvironment and prevents repair of the damaged BBB, which is ultimately attributed to the pathological formation and growth of brain metastatic cancers such as melanoma (26). Mechanisms involving the repair of the BBB through increased angiogenesis and vasculogenesis represent effective therapies for attenuation of developing brain metastatic cancers. DISRUPTED BBB IN CANCER AND INFLAMMATION The BBB possesses a sophisticated system composed of microvascular endothelium joined together by gap junctions (connexins), astrocytes, neurons, and basement membrane (32). This system functions to protect the brain from toxins and microorganisms, regulate inflammationassociated molecules, and supply the brain with necessary nutrients. The nature of the BBB is maintained by tight junctions, which provide the BBB with selective permeability and controls the flow of ions, nutrients, and cells into the brain (1,11). Brain tumors have been shown to disrupt the BBB utility, amplifying abnormal permeability, particularly at the site of the tumor (10,20). To colonize the brain parenchyma, metastatic tumor cells must penetrate the threshold of the BBB. It has been posited that adhering tumor cells retract the endothelium of the BBB, altering its integrity and plasticity. Indeed, primary and metastatic brain tumors have been exhibited to
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decrease the expression of tight junction proteins resulting in a leaky BBB (25,30). Disruption of the BBB permeability has been observed in breast cancer patients following metastasis to the brain (44). As developed tumors continue to enlarge, they rapidly outgrow their vasculature and become deprived of oxygen and essential nutrients. The resulting hypoxia promotes the migration/translocation of prototyped inflammatory cells, such as tumorassociated macrophages, into cancer lesions (16). These tumor-associated macrophages, a source of inflammationassociated cytokines, then stimulate the generation and development of tumor-supporting vasculature, which facilitates the growth of the tumor (7). Unregulated and persistent recruitment, due to disruption of the BBB, of such aforementioned proinflammatory compounds leads to tumor growth and further BBB systematic degradation (26,41). Inflammation-associated cytokines, such as interleukin-6 (IL-6), encoded by a family of small noncoding RNA or microRNA, regulate the translation of transcription factors (e.g., miR142-3p) (9), enhance cell proliferation, and inhibit the apoptosis signaling pathway by modulating the expression of tumor-suppressive genes and oncogenes (35,36). As the BBB continues to be degraded, the selective permeability of the barrier declines. While it is understood that this decreased selectivity permits increased entry of chemotherapy agents (43), several studies have revealed no increase in the efficacy of chemotherapy agents used in association with a compromised BBB (6,18,23,24,34). Repair of a leaky BBB caused by metastatic cancer restricts the entry of growth-enhancing proinflammatory molecules without further inhibiting the delivery of chemotherapeutic agents. BBB REPAIR IN CANCER VIA CELL THERAPY Transplantation of bone marrow-derived endothelial progenitor cells, and engineering these cells to improve on angiogenesis and vasculogenesis, may provide an effective method for repairing the damaged BBB. Bone marrow-derived stem cells, especially those with the endothelial progenitor cell phenotype, have been demonstrated to repair the BBB and produce normal permeability following cerebral ischemia in rodents (8). A similar method of repair may be instituted in the case of leaky BBB associated with metastatic tumor formation. BBB breakdown occurs within brain metastases and allows inflammatory factors from the systemic circulation to penetrate the BBB, increasing the proliferation rate of the metastatic brain cancers. Modeling of the brain metastatic cancers will be required to test this hypothesis. In this regard, mouse melanoma cell line B16F10 can be infused into a common inbred strain (C57b1 mice) via intracarotid injection to generate an experimental model of brain metastatic cancers such as melanoma. Endpoint assays, including in situ hybridization, quantitative real-time polymerase
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chain reaction, and immunoreactive analyses, will be key outcome parameters to evaluate tumor growth, BBB leakage, and inflammation/immune response. Recognizing this leaky BBB-mediated inflammation as exacerbating, we hypothesize that stem cell therapy will repair the BBB via angiogenesis, suppressing brain inflammation and ultimately reducing the brain tumor growth rate. Evidence suggests that bone marrow-derived mesenchymal stromal cells (MSCs) enhance BBB integrity (27), selectively target malignant brain tumor sites to sequester cancer cell proliferation (28), and that coculture with human neuronal stem cells significantly inhibits the growth of brain metastasis from breast cancer (38). Therapeutic tools using allogeneic human bone marrow-derived MSCs transfected with interferon-b (IFN-b), inhibit tumor growth, suppress pulmonary metastasis, and prolong the longevity (4). Combination therapy of IFN-b/MSCs directly regulates the proliferation of melanoma, which does not require downregulation of the immune system (39) and stands as a potent treatment for melanoma. Evaluating the optimal route of stem cell transplantation may initially require direct implantation into the cells of an experimentally induced focal metastatic brain tumor. Once efficacy is demonstrated, minimally invasive delivery (e.g., intravenous or intra-arterial) will need to be assessed in order to capture the clinical manifestation of most metas tasized brain cancers characterized by widespread infiltration, as opposed to localized deposition. Moreover, the timing of administration (e.g., acute vs. delayed metastasis) will also need optimization in order to envisage the clinical treatment regimen. Transplantation of MSCs (2) (especially those cells with endothelial progenitor cell phenotype) engineered with genes directed at enhancing angiogenesis and/or vasculogenesis is deemed appropriate in repairing the BBB and reducing the brain inflammation associated with brain tumors (Fig. 1). Assays of BBB repair and downregulation of brain inflammation should be assessed in both acute and delayed post-B16F10 injection time points in order to determine a therapeutic window for stem cell transplantation in treating brain metastasis of melanoma. The aforementioned endpoint assays should be combined with evaluation of the fate of the grafted stem cells to actually delineate therapeutic efficacy of the transplants, but also to assess safety. This research design should allow us to gain insights into the benefits of cell therapy, and optimal timing and dose of stem cell transplant, which can be used in designing clinical trials for treating brain metastasis derived from melanoma. There are still concerns regarding the use of stem cells to treat any cancer; therefore, transplanted cells could support angiogenesis or vasculogenesis that lends itself to tumor growth, provide trophic support for tumors, or the stem cells themselves could become cancerous. However, our challenge into the use of stem cells to restore the BBB
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following metastatic brain cancer and to characterize mechanism of action via the bystander effects is crucial to the development of such therapies (27,28,39). CONCLUSIONS We mentioned that tumor-derived disruption of the BBB may result in increased brain inflammation that exacerbates the growth rate of brain metastases. Bone marrow-derived endothelial progenitor cells genetically manipulated to enhance angiogenesis and vasculogensis are expected to repair the leaky BBB, ameliorate brain inflammation, and decrease recruitment of tumor-associated macrophages. The basic science, translational, and clinical significance of this envisioned stem cell therapy is the demonstration that bone marrow-derived endothelial progenitor cells will stimulate angiogenesis and vasculogenesis that leads to repair of a leaky BBB. Inflammation within the brain will decrease and growth of cancerous tumors will lessen, thereby representing a novel stem cell therapy for brain metastatic cancers from melanoma. ACKNOWLEDGMENTS: C.V.B. is supported by NIH NINDS 1R01NS071956-01, DOD TATRC W81XWH-11-1-0634, James and Esther King Biomedical Research Program 09KB-01-23123 and 1KG01-33966, and USF Department of Neurosurgery and Brain Repair Funds. Y.K. is supported by USF OR and I HSC18330 and COM HSC-18300. C.V.B, T.B.F, and P.R.S have patents and patent applications related to stem cell therapy.
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