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Osteoblasts; Tumor-Induced Osteolysis; Chemokines; Stromal Cells.

Introduction

Breast cancer is a heterogeneous disease characterized by the uncontrolled growth of malignant cells in the breast tissue. While advancements in early detection and treatment have improved outcomes for many breast cancer patients, metastasis remains a significant challenge. Bone metastasis occurs in approximately 70% of patients with advanced breast cancer, leading to skeletal-related events such as pain, pathological fractures, and spinal cord compression. The establishment of bone metastases involves a complex interplay between breast cancer cells and the bone microenvironment, with the endosteal niche playing a critical role in this process. Breast cancer is a formidable challenge in modern oncology, affecting millions of women worldwide and representing a significant cause of morbidity and mortality. While advancements in early detection and treatment have improved outcomes for many patients, the development of metastatic disease remains a major clinical hurdle [1,2]. Among the various sites of metastasis, the bone represents one of the most common destinations for breast cancer cells, contributing significantly to disease burden and diminished quality of life. The process of breast cancer bone metastasis involves a complex interplay of molecular and cellular interactions between tumor cells and the bone microenvironment. The bone microenvironment, or bone marrow niche, is a dynamic and heterogeneous milieu consisting of multiple cell types and extracellular matrix components. Within this niche, the endosteal region, located along the inner surface of the bone, emerges as a critical player in the pathogenesis of bone metastasis. This review aims to explore the intricate relationship between breast cancer cells and the endosteal niche within the bone microenvironment, shedding light on the molecular mechanisms underlying bone metastasis. By understanding the dynamic interplay between tumor cells and the bone microenvironment, we can identify novel therapeutic targets and develop more effective strategies for the prevention and treatment of breast cancer bone metastasis [3,4].

Methodology

Bone marrow niches: Bone marrow niches are specialized microenvironments within the bone marrow that support the growth, differentiation, and maintenance of various cell populations, including hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). These niches provide the necessary signals and physical support for the regulation of stem cell behavior, such as self-renewal and differentiation into different blood cell types or bone-forming cells. The interactions between cells within these niches play crucial roles in normal hematopoiesis, immune function, and bone homeostasis [5-7].

Physiological niche: In bone, the physiological niche is composed of several local environments including the endosteal niche and the vascular niche. The endosteal niche lines the trabecular and endocortical bone surface and consists of osteoblasts that form new bone and osteoclasts that resorb the bone. Osteoblasts are derived from MSCs in a process tightly controlled by various transcription factors and signaling pathways. The key transcription factors Runx2 and osterix (Osx) promote MSC commitment to osteoprogenitors and further differentiation to mature osteoblasts. Mature osteoblasts secrete bone matrix proteins including collagen I (Col1), alkaline phosphatase (ALP) and osteocalcin, and contribute to bone formation. Mature osteoblasts can be embedded in the bone matrix as osteocytes that function as mechanosensory cells and contribute to bone remodeling. Alternatively, osteoblasts can adapt a quiescent state on the bone surface as bone lining cells or undergo apoptosis. Osteoblast differentiation is promoted by various paracrine factors including parathyroid hormone (PTH) and wingless (Wnt) proteins that activate the respective signaling pathways. Besides osteoblasts, MSCs can give rise to other mesenchymal cell populations including adipocytes, chondrocytes and myocytes. Adipocytes are a frequent cell type in the bone marrow and an inverse relationship has been shown to occur between osteogenesis and adipogenesis of MSCs [8,9].

Bone-resorbing osteoclasts are multinucleated cells of hematopoietic origin. Osteoclast differentiation is supported by various cytokines including the macrophage colony-stimulating factor (MCS-F) and the receptor activator of nuclear factor kappa-B ligand (RANKL) that are produced by osteoblasts. In turn, osteoclasts secrete factors such as Wnt 10b, sphingosine-1-phosphate and bone morphogenic protein 6 (BMP-6) to regulate osteoblast differentiation and function. Additionally, bone matrix-derived factors including but not limited to TGF-ß, insulin like growth factors (IGFs) and bone morphogenic proteins (BMPs) are released during osteoclast-mediated bone resorption and can modify osteoblast progenitors. Detailed coupling mechanisms between osteoblasts and osteoclasts are reviewed in. Through these coordinated actions bone formation and resorption are often coupled under physiological conditions. In addition to its role in bone remodeling, the endosteal niche has been proposed to maintain hematopoietic stem cells (HSCs) in a quiescent state [10].

Discussion

Breast cancer bone metastasis involves a complex interplay between cancer cells and the bone microenvironment, particularly the endosteal niche. The endosteal niche refers to the specialized microenvironment surrounding the bone surface, which plays a crucial role in regulating bone remodeling and homeostasis. When breast cancer cells metastasize to the bone, they interact with various components of the endosteal niche, including osteoblasts, osteoclasts, and bone marrow stromal cells. One of the key mechanisms through which breast cancer cells interact with the endosteal niche is through the release of various signaling molecules, including cytokines, growth factors, and chemokines. These molecules can stimulate osteoclast activity, leading to bone resorption, as well as promote the recruitment and proliferation of tumor-supportive cells within the bone marrow. Additionally, breast cancer cells can also directly interact with osteoblasts and bone marrow stromal cells, leading to alterations in the bone microenvironment that further support tumor growth and survival. For example, cancer cells can induce the expression of factors such as RANK ligand and interleukin-6, which promote osteoclast genesis and bone resorption. This creates a vicious cycle of bone destruction and tumor growth, ultimately leading to the development of osteolytic lesions characteristic of breast cancer bone metastasis. Furthermore, the endosteal niche provides a fertile environment for the establishment of disseminated tumor cells (DTCs) and the formation of metastatic colonies. The unique anatomical and physiological features of the endosteal niche, including hypoxia and the presence of nichespecific signaling molecules, create a sanctuary for DTCs, allowing them to evade immune surveillance and therapeutic interventions.

Conclusion

In conclusion, breast cancer bone metastasis is a complex process involving dynamic interactions between cancer cells and the endosteal niche. Understanding the molecular and cellular mechanisms underlying these interactions is essential for the development of targeted therapies aimed at disrupting the bone metastatic cascade. Targeting key signaling pathways involved in osteoclast activation, such as the RANK/RANKL pathway, represents a promising therapeutic strategy for preventing bone destruction and inhibiting tumor growth in patients with breast cancer bone metastasis. Additionally, strategies aimed at targeting the bone marrow microenvironment and disrupting the supportive niche for DTCs may help prevent the establishment and progression of bone metastases. Overall, a comprehensive understanding of the role of the endosteal niche in breast cancer bone metastasis is crucial for the development of effective therapeutic interventions to improve patient outcomes and quality of life.

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