Philip K. Lim

Gap Junction–Mediated Import of MicroRNA from Bone Marrow Stromal Cells Can Elicit Cell Cycle Quiescence in Breast Cancer Cells

Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G(0) phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases.

The Microenvironmental Effect in the Progression, Metastasis, and Dormancy of Breast Cancer: A Model System within Bone Marrow

Despite diagnostic advances, breast cancer remains the most prevalent cancer among women in the United States. The armamentarium of treatment options for metastatic disease is limited and mostly ineffective with regards to eradicating cancer. However, there have been novel findings in the recent literature that substantiate the function of the microenvironment in breast cancer progression and the support of metastasis to tertiary sites such as bone marrow. The uncovered significance of the microenvironment in the pathophysiology of breast cancer metastasis has served to challenge previously widespread theories and introduce new perspectives for the future research to eradicate breast cancer. This paper delineates the current understanding of the molecular mechanisms involved in the interactions between breast cancer cells and the microenvironment in progression, metastasis, and dormancy. The information, in addition to other mechanisms described in bone marrow, is discussed in the paper.

microRNAs, Gap Junctional Intercellular Communication and Mesenchymal Stem Cells in Breast Cancer Metastasis

The failed outcome of autologous bone marrow transplantation for breast cancer opens the field for investigations. This is particularly important because the bone marrow could be a major source of cancer cells during tertiary metastasis. This review discusses subsets of breast cancer cells, including those that enter the bone marrow at an early period of disease development, perhaps prior to clinical detection. This population of cells evades chemotherapeutic damage even at high doses. An understanding of this population might be crucial for the success of bone marrow transplants for metastatic breast cancer and for the eradication of cancer cells in bone marrow. In vivo and in vitro studies have demonstrated gap junctional intercellular communication (GJIC) between bone marrow stroma and breast cancer cells. This review discusses GJIC in cancer metastasis, facilitating roles of mesenchymal stem cells (MSCs). In addition, the review addresses potential roles for miRNAs, including those already linked to cancer biology. The literature on MSCs is growing and their links to metastasis are beginning to be significant leads for the development of new drug targets for breast cancer. In summary, this review discusses interactions among GJIC, miRNAs and MSCs as future consideration for the development of cancer therapies.

Challenges in the development of future treatments for breast cancer stem cells.

The recurrence of tumors after years of disease-free survival has spurred interest in the concept that cancers may have a stem cell basis. Current speculation holds that as few as 0.1% of the tumor mass may be chemoresistant and radioresistant, harboring stem-like properties that drive tumor survival, development, and metastasis. There are intense investigations to characterize cancer stem cells on the basis of self-renewal and multi-lineage differentiation. Thus far, no successful targeted therapies have been developed and reached the clinic, but as these cells are isolated and characterized, insights may be unraveled. In this review, we discuss the controversy over the origins of the cancer stem cell hypothesis and the unforeseen factors that may facilitate breast cancer stem cell survival and metastasis. We discuss the role of tumor microenvironment, including carcinoma-associated fibroblasts, epigenetic factors, and the Th1/Th2 balance, in supporting breast cancer stem cells. In addition, we have incorporated ideas on the epithelial-to-mesenchymal transition in metastatic dissemination of epithelial malignancies. This area is relevant since breast cancer stem cells have been suggested to revert to a mesenchymal phenotype during the progression of cancer. Finally we discuss prospects of developing targeted therapy including novel treatment modalities such as oncolytic viral therapy, differentiation therapy, and nanotechnology.

Neurogenesis: role for microRNAs and mesenchymal stem cells in pathological states.

Implantation of adult human mesenchymal stem cells (MSCs) to treat neural disorders shows promise. Depending on their microenvironment, MSCs could potentially be used for the repair and/or replacement of neurons in traumatic brain injury or the treatment of Parkinsons disease. This cross-disciplinary review incorporates aspects of neuroscience, stem cell biology, cancer biology and immunology to discuss interactions between inflammatory mediators and MSCs. We first discuss the role of microRNAs (miRNAs) in neurological development. Secondly, we discuss the ability of MSCs to transdifferentiate into functional neurons, which are regulated by miRNAs, and the implications of these cells for the therapy of neuropathological states. The administration of effective and safe MSC therapy must acknowledge immune mediators that may predispose the early differentiating MSCs to oncogenic insults. Thus, we discuss a key gene, RE-1 silencing transcription factor (REST), based on its dual role in neurogenesis and cancer development. Immune mediators could be central to MSC responses within a region of tissue injury and are also discussed in detail. Exploring the predisposition of MSCs to oncogenesis is critical for translational science since the implementation of safeguarding measures prior to therapy can lead to the successful delivery of stem cells to patients. The method by which MSCs could be applied for future therapies might require trans-disciplinary approaches for personalized treatments.

Chapter 17:Effective Tissue Repair and Immunomodulation by Mesenchymal Stem Cells within a Milieu of Cytokines

Mesenchymal stem cells (MSCs) appear to be safe for cellular therapy across allogeneic barrier. MSCs have the potential for tissue regeneration of mesodermally-derived cells, such as bone, cartilage, and adipose, and also cells of ectodermal origin. The immune properties of MSCs are relevant to their potential application for hyper immune diseases such as the treatment of autoimmune and other inflammatory disorders. MSCs exert immune suppressor functions such as decrease in T-cell proliferation and effector cell function, with concomitant expansion of regulatory T cells. In light of dampened outcome from recent clinical trials with MSCs, this chapter discusses how the immune microenvironment and local cytokine milieu can dictate the effects of MSCs on various biological processes. For example, variations in the local concentration of interferon-γ(IFN-γ) can influence the antigen-presenting function of MSCs, thereby making MSCs immune suppressor or enhancer. The diverse effects of MSCs as well as the potential confounds by an inflamed microenvironment are highlighted to emphasize the need to understand the basic biology of MSCs for effective treatment for tissue repair or resetting the immune system.