ReviewThe lymph node microenvironment and its role in the progression of metastatic cancer
Introduction
Cancer metastasis is a complex, multi step process that involves the dissemination of cancer cells from the primary site to distant organs [1]. Several recent studies have advanced our knowledge of the spread of tumor cells via the blood stream, however, less is known about the process of lymphatic metastasis. Mounting evidence suggests that lymphatic metastasis is not an entirely passive process as previously hypothesized, but is regulated at multiple steps including the transit of tumor cells via the lymphatic vessels and the successful seeding in draining lymph nodes [2]. The presence of tumor cells in regional or sentinel lymph nodes (SLN) has important clinical significance as it is associated with disease progression, poor prognosis and often determines the choice of therapies [3], [4], [5]. The increasing recognition of the importance of lymph node metastasis in cancer biology has prompted recent studies to unravel the molecular signals and cellular changes involved in this complex process. Some of these changes include lymphangiogenesis, the expansion of immunosuppressive cells, up-regulation of chemokines and cytokines, and blood vessel remodeling in the lymph node. These events help facilitate tumor cell entry, colonization and survival in the lymph node. However, the ultimate fate of tumor cells in the lymph node is still controversial [6].
Several studies have elucidated how tumor cells home to the lymph node by chemokine signals that are often secreted by stromal or immune cells in the lymph node microenvironment [7]. In addition to promoting tumor cell residence in the lymph node, chemokines play an important role in modulating immune or stromal cell activity. Furthermore, the role of lymphatic vessels and lymphangiogenesis in altering the local inflammatory response and promoting an immunosuppressive microenvironment in the lymph node is critical for tumor cell dissemination to this organ [8]. Recent progress in lymphatic vessel biology, including the development of sophisticated intravital imaging techniques for monitoring the process of lymphangiogenesis and lymphatic metastases has led to the appreciation of the lymphatic system as a major contributor to cancer progression [9], [10], [11], [12], [13], [14], [15]. In this review we discuss recent progress in our understanding of the mechanisms involved in lymph node metastasis and the potential role of the lymph node in facilitating tumor cell proliferation and metastases to distant organs.
Section snippets
The lymph node, lymphatic vessels and lymphangiogenesis
The lymphatic vasculature is a series of vessels throughout the body that play important roles in tissue homeostasis, fluid balance, immune function, absorption of dietary fat and lipid transport. In addition to their role in normal physiology, lymphatic vessels play critical roles in pathological conditions including inflammation and cancer [16], [17]. Lymphatic endothelial cells express several molecular markers that include LYVE-1, Prox1, podoplanin (gp38), VEGFR-2, VEGFR-3, neuropilin-2,
Chemokine signaling in lymph node metastases
After cancer cells arrive in the lymph node, further changes occur (Fig. 1). Chemical signals known as chemokines help direct cells, including cancer cells, to new locations. Chemokines are a superfamily of cytokine-like molecules that can induce cytoskeletal rearrangement and directional migration of cells via their association with specific G-protein coupled receptors. Chemokines play critical roles in the migration, proliferation and maturation of immune cells in the lymph node. A growing
Evading immune surveillance in the lymph node
Naïve lymph nodes are the site of immune regulation where foreign, pathogenic or self-antigens accumulate. Optimal interactions between antigen-loaded-dendritic cells (DCs) and effector T lymphocytes in the lymph node facilitate adaptive immune responses that eliminate foreign and pathogenic antigens. In cancer, functional lymphatic vessels on the periphery of tumors are the physical connection between the primary tumor and SLNs. Rogue tumor cells have evolved ways of evading immune
Clonal dissection of lymph node metastases in solid tumors
There is much speculation about the chronological sequence of events in tumor cell metastasis from a primary location to a secondary or tertiary site. Several studies have performed lineage tracing and genomic sequencing on primary and metastatic tumors in an attempt to understand this phenomenon. A recent study characterized the clonal evolution of tumor cells in a genetically engineered mouse model of small cell lung carcinoma at metastatic sites including the lymph node and liver [88]. This
Lymph node metastases: clinical perspectives
Primary tumor resection and axillary lymph node dissection (ALND) have been part of the standard treatment for breast cancer patients with metastases in the SLN. These surgeries attempt to eliminate all disease provided the cancer is in the early stages and has not metastasized to distant organs. However, ALND has several devastating short-term and long-term side effects including seromas, infections, reduced arm movement and lymphedema [90]. Due to these complications, two recent randomized
Targeting lymph node metastases
Controlling the size of lymph node metastasis is important since recent clinical data have shown that breast cancer patients with micrometastases (≤2 mm) in their SLNs have a reduced incidence of distant metastasis compared to those with macrometastasis [95]. Angiogenesis is required for invasive tumor growth and metastasis of the primary tumor [96]. We, and others have previously shown that antiangiogenic therapy was not as effective in stopping the initial seeding of tumor cells in the lymph
Conclusions and future perspectives
Studies focused on understanding the process of lymphatic metastases and the role of the lymph node in tumor progression in the past decade have given us insights into the importance of these organs in cancer biology. Metastasis to the lymph node is preceded by changes in the lymph node microenvironment. A more comprehensive understanding of the molecular signals in the premetastatic lymph node niche that facilitate tumor metastasis could provide therapeutic targets to control lymph node
Acknowledgements
This work was supported by the National Institutes of Health DP2OD008780 (TPP), R00CA137167 (TPP), R21AI097745 (TPP), National Cancer Institute Federal Share/MGH Proton Beam Income on C06 CA059267 (TPP), UNCF-Merck Science Initiative Postdoctoral Fellowship (D.J.) and Burroughs Wellcome Postdoctoral Enrichment Program Award (D.J.). We would like to acknowledge Sonia Pereira for her help with the graphical illustration.
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