Melanoma-derived mediators can foster the premetastatic niche: crossroad to lymphatic metastasis.

The natural history of advanced malignant melanoma demonstrates that, in most cases, widespread tumor dissemination is preceded by regional metastases involving tumor-draining lymph nodes [sentinel lymph nodes (SLNs)]. Under physiological conditions, LNs play a central role in immunosurveillance to non-self-antigens to which they are exposed via afferent lymph. The dysfunctional immunity in SLNs is mediated by tumor secretory factors that allow the survival of metastatic melanoma cells within the LN by creating a premetastatic niche (PMN). Recent studies outline the altered microenvironment of LNs shaped by melanoma mediators. Here, we discuss tumor secretory factors involved in subverting tumor immunity and remodeling LNs and highlight emerging therapeutic strategies to reinvigorate antitumoral immunity in SLNs.

Tumor-polarized GPX3+ AT2 lung epithelial cells promote premetastatic niche formation.

The cellular and molecular components required for the formation of premetastatic niche (PMN) to promote lung metastasis need to be further investigated. Lung epithelial cells have been reported to exhibit immunomodulatory roles in lung homeostasis and also to mediate immunosuppressive PMN formation in lung metastasis. Here, by single-cell sequencing, we identified a tumor-polarized subpopulation of alveolar type 2 (AT2) epithelial cells with increased expression of glutathione peroxidase 3 (GPX3) and high production of interleukin (IL)-10 in the PMN. IL-10-producing GPX3+ AT2 cells inhibited CD4+ T cell proliferation but enhanced regulatory T cell generation. Mechanistically, tumor exosome-inducing GPX3 expression is required for GPX3+ AT2 cells to preferentially produce IL-10 by stabilizing hypoxia-inducible factor 1 (HIF-1α) and promoting HIF-1α-induced IL-10 production. Accordingly, conditional knockout of GPX3 in AT2 cells suppressed lung metastasis in spontaneous metastatic models. Together, our findings reveal a role of tumor-polarized GPX3+ AT2 cells in promoting lung PMN formation, adding insights into immune evasion in lung metastasis and providing potential targets for the intervention of tumor metastasis.

Neutrophils in the premetastatic niche: key functions and therapeutic directions.

Metastasis has been one of the primary reasons for the high mortality rates associated with tumours in recent years, rendering the treatment of current malignancies challenging and representing a significant cause of recurrence in patients who have undergone surgical tumour resection. Halting tumour metastasis has become an essential goal for achieving favourable prognoses following cancer treatment. In recent years, increasing clarity in understanding the mechanisms underlying metastasis has been achieved. The concept of premetastatic niches has gained widespread acceptance, which posits that tumour cells establish a unique microenvironment at distant sites prior to their migration, facilitating their settlement and growth at those locations. Neutrophils serve as crucial constituents of the premetastatic niche, actively shaping its microenvironmental characteristics, which include immunosuppression, inflammation, angiogenesis and extracellular matrix remodelling. These characteristics are intimately associated with the successful engraftment and subsequent progression of tumour cells. As our understanding of the role and significance of neutrophils in the premetastatic niche deepens, leveraging the presence of neutrophils within the premetastatic niche has gradually attracted the interest of researchers as a potential therapeutic target. The focal point of this review revolves around elucidating the involvement of neutrophils in the formation and shaping of the premetastatic niche (PMN), alongside the introduction of emerging therapeutic approaches aimed at impeding cancer metastasis.

Circulating Tumor Cells: Does Ion Transport Contribute to Intravascular Survival, Adhesion, Extravasation, and Metastatic Organotropism?

Survival in the circulation, extravasation from vasculature, and colonizing new tissues represent major steps of the metastatic cascade and pose a big challenge for metastasizing tumor cells. Tumor cells circulating in blood and lymph vessels need to overcome anoikis, cope with mechanical stimuli including shear stress, and defeat attacks by the immune system. Once adhered to the vessel wall, a circulating tumor cell (CTC) can trick the endothelial cells into loosening their intercellular junctions so that the endothelium becomes penetrable for the tumor cell. Since tumor cells tend to metastasize to predestinated target organs and tissues, called organotropism, the distribution of metastases is anything but random. The molecular-physiological mechanisms underlying CTC survival, extravasation, and organotropism are very likely to include the presence and activity of ion channels/transporters due to the latter's key function in cytophysiological processes. To date, a very limited number of studies explicitly show the involvement of ion transport. This review describes the contribution of ion channels and transporters to CTC survival, extravasation, and organotropism where known and possible. In addition, supposed connections between ion transport and CTC behavior are demonstrated and imply the potential to be therapeutically taken advantage of.

mir-605-3p prevents liver premetastatic niche formation by inhibiting angiogenesis via decreasing exosomal nos3 release in gastric cancer.

BACKGROUND: Cancer-induced pre-metastatic niches (PMNs) play a decisive role in promoting metastasis by facilitating angiogenesis in distant sites. Evidence accumulates suggesting that microRNAs (miRNAs) exert significant influence on angiogenesis during PMN formation, yet their specific roles and regulatory mechanisms in gastric cancer (GC) remain underexplored. METHODS: miR-605-3p was identified through miRNA-seq and validated by qRT-PCR. Its correlation with the clinicopathological characteristics and prognosis was analyzed in GC. Functional assays were performed to examine angiogenesis both in vitro and in vivo. The related molecular mechanisms were elucidated using RNA-seq, immunofluorescence, transmission electron microscopy, nanoparticle tracking analysis, enzyme-linked immunosorbent assay, luciferase reporter assays and bioinformatics analysis. RESULTS: miR-605-3p was screened as a candidate miRNA that may regulate angiogenesis in GC. Low expression of miR-605-3p is associated with shorter overall survival and disease-free survival in GC. miR-605-3p-mediated GC-secreted exosomes regulate angiogenesis by regulating exosomal nitric oxide synthase 3 (NOS3) derived from GC cells. Mechanistically, miR-605-3p reduced the secretion of exosomes by inhibiting vesicle-associated membrane protein 3 (VAMP3) expression and affects the transport of multivesicular bodies to the GC cell membrane. At the same time, miR-605-3p reduces NOS3 levels in exosomes by inhibiting the expression of intracellular NOS3. Upon uptake of GC cell-derived exosomal NOS3, human umbilical vein endothelial cells exhibited increased nitric oxide levels, which induced angiogenesis, established liver PMN and ultimately promoted the occurrence of liver metastasis. Furthermore, a high level of plasma exosomal NOS3 was clinically associated with metastasis in GC patients. CONCLUSIONS: miR-605-3p may play a pivotal role in regulating VAMP3-mediated secretion of exosomal NOS3, thereby affecting the formation of GC PMN and thus inhibiting GC metastasis.

Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion.

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.

Extracellular vesicles in cancer therapy.

Extracellular vesicles (EVs), including a variety of membrane-enclosed nanosized particles carrying cell-derived cargo, mediate a major type of intercellular communication in physiological and pathological processes. Both cancer and non-cancer cells secrete EVs, which can travel to and influence various types of cells at the primary tumor site as well as in distant organs. Tumor-derived EVs contribute to cancer cell plasticity and resistance to therapy, adaptation of tumor microenvironment, local and systemic vascular remodeling, immunomodulation, and establishment of pre-metastatic niches. Therefore, targeting the production, uptake, and function of tumor-derived EVs has emerged as a new strategy for stand-alone or combinational therapy of cancer. On the other hand, as EV cargo partially reflects the genetic makeup and phenotypic properties of the secreting cell, EV-based biomarkers that can be detected in biofluids are being developed for cancer diagnosis and for predicting and monitoring tumor response to therapy. Meanwhile, EVs from presumably safe sources are being developed as delivery vehicles for anticancer therapeutic agents and as anticancer vaccines. Numerous reviews have discussed the biogenesis and characteristics of EVs and their functions in cancer. Here, I highlight recent advancements in translation of EV research outcome towards improved care of cancer, including developments of non-invasive EV-based biomarkers and therapeutic agents targeting tumor-derived EVs as well as engineering of therapeutic EVs.

The interplay between tumor and nodal microenvironments for the formation of nodal premetastatic niche in head and neck cancer.

Head and neck cancer (HNC) encompasses a number of malignancies originating in the head and neck area. In patients with HNC, cervical lymph nodes constitute metastatic sites for cancer cells that escape primary tumors. The premetastatic niche (PMN) is a crucial concept in understanding metastatic disease. PMN refers to the microenvironment resulting mainly from primary tumor cells to foster metastatic tumor cell growth at a distant organ. Tumor microenvironment (TME) plays an important part in the pathogenesis of PMN. A significant prognostic factor is the close association between metastases of lymph nodes and organ dissemination in many different malignancies. The nodal premetastatic niche (NPMN) is a particular type of PMN located within the lymph nodes. NPMN formation is specifically important in HNC as regional lymph node metastasis commonly occurs. The formation happens when tumor cells create a supportive microenvironment within lymph nodes, facilitating their survival, growth, spread, and invasion. This complex mechanism involves multiple steps and cellular interactions between the primary tumor and tumor microenvironment. Several extracellular matrix (ECM) macromolecules, cytokines, and growth factors are implicated in this process. The aim of this article is to present the most recent data on the regulation of the lymph node PMN at molecular and cellular levels in HNC, as well as insights with respect to the relationship between primary tumor cells and the microenvironment of lymph nodes, and the formation of NPMN. We also critically discuss on potential targets for preventing or disrupting nodal metastases and identify potential biomarkers for predicting HNC outcomes.

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs.

Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the premetastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous triple-negative breast cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC; EVsCSC and EVsDCC , respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.

Local radiotherapy for murine breast cancer increases risk of metastasis by promoting the recruitment of M-MDSCs in lung.

BACKGROUND: Radiotherapy is one of the effective methods for treatment of breast cancer; however, controversies still exist with respect to radiotherapy for patients with TNBC. Here, we intend to explore the mechanism by which local radiotherapy promotes the recruitment of M-MDSCs in the lung and increases the risk of lung metastasis in TNBC tumor-bearing mice. METHODS: A single dose of 20 Gy X-ray was used to locally irradiate the primary tumor of 4T1 tumor-bearing mice. Tumor growth, the number of pulmonary metastatic nodules, and the frequency of MDSCs were monitored in the mice. Antibody microarray and ELISA methods were used to analyze the cytokines in exosomes released by irradiated (IR) or non-IR 4T1 cells. The effects of the exosomes on recruitment of MDSCs and colonization of 4T1 cells in the lung of normal BALB/c mice were observed with the methods of FCM and pathological section staining. T lymphocytes or 4T1 cells co-cultured with MDSCs were performed to demonstrate the inhibitory effect on T lymphocytes or accelerative migration effect on 4T1 cells. Finally, a series of in vitro experiments demonstrated how the exosomes promote the recruitment of M-MDSCs in lung of mice. RESULTS: Even though radiotherapy reduced the burden of primary tumors and larger lung metastatic nodules (≥ 0.4 mm2), the number of smaller metastases (< 0.4 mm2) significantly increased. Consistently, radiotherapy markedly potentiated M-MDSCs and decreased PMN-MDSCs recruitment to lung of tumor-bearing mice. Moreover, the frequency of M-MDSCs of lung was positively correlated with the number of lung metastatic nodules. Further, M-MDSCs markedly inhibited T cell function, while there was no difference between M-MDSCs and PMN-MDSCs in promoting 4T1 cell migration. X-ray irradiation promoted the release of G-CSF, GM-CSF and CXCl1-rich exosomes, and facilitated the migration of M-MDSCs and PMN-MDSCs into the lung through CXCL1/CXCR2 signaling. While irradiated mouse lung extracts or ir/4T1-exo treated macrophage culture medium showed obvious selective chemotaxis to M-MDSCs. Mechanistically, ir/4T1-exo induce macrophage to produce GM-CSF, which further promoted CCL2 release in an autocrine manner to recruit M-MDSCs via CCL2/CCR2 axis. CONCLUSIONS: Our work has identified an undesired effect of radiotherapy that may promote immunosuppressive premetastatic niches formation by recruiting M-MDSCs to lung. Further studies on radiotherapy combined CXCR2 or CCR2 signals inhibitors were necessary.

Extracellular Vesicles Are Important Mediators That Regulate Tumor Lymph Node Metastasis via the Immune System.

Extracellular vesicles (EVs) are particles with a lipid bilayer structure, and they are secreted by various cells in the body. EVs interact with and modulate the biological functions of recipient cells by transporting their cargoes, such as nucleic acids and proteins. EVs influence various biological phenomena, including disease progression. They also participate in tumor progression by stimulating a variety of signaling pathways and regulating immune system activation. EVs induce immune tolerance by suppressing CD8+ T-cell activation or polarizing macrophages toward the M2 phenotype, which results in tumor cell proliferation, migration, invasion, and metastasis. Moreover, immune checkpoint molecules are also expressed on the surface of EVs that are secreted by tumors that express these molecules, allowing tumor cells to not only evade immune cell attack but also acquire resistance to immune checkpoint inhibitors. During tumor metastasis, EVs contribute to microenvironmental changes in distant organs before metastatic lesions appear; thus, EVs establish a premetastatic niche. In particular, lymph nodes are adjacent organs that are connected to tumor lesions via lymph vessels, so that tumor cells metastasize to draining lymph nodes at first, such as sentinel lymph nodes. When EVs influence the microenvironment of lymph nodes, which are secondary lymphoid tissues, the immune response against tumor cells is weakened; subsequently, tumor cells spread throughout the body. In this review, we will discuss the association between EVs and tumor progression via the immune system as well as the clinical application of EVs as biomarkers and therapeutic agents.

Liver prometastatic reaction: Stimulating factors and responsive cancer phenotypes.

Cancer is first a localized tissue disorder, whose soluble and exosomal molecules and invasive cells induce a host response providing the stromal components of the primary tumor microenvironment (TME). Once the TME is developed, cancer-derived molecules and cells can more efficiently spread out and a whole-body response takes place, whose pathophysiological changes may result in a paraneoplastic syndrome. Remote organ-specific prometastatic reactions may also occur at this time, facilitating metastatic activities of circulating tumor cells (CTCs) through premetastatic niche development at targeted organs. However, additional signaling factors from the inter-organ communication network involved in the pathophysiology and comorbidities of cancer patients may also regulate prometastatic reaction-stimulating effects of cancer and non-cancer tissue factors. This article provides a conceptual overview of our ongoing clinical research on the liver prometastatic reaction (LPR) of patients with colorectal cancer (CRC), their portal vein- and hepatic artery-driven LPR-Stimulating Factors (LPR-SF), and their resulting LPR-derived Metastasis-Stimulating Factors (LPR-MSF) acting on liver-invading CRC cells. In addition, we also provide new insights on the molecular subtyping of LPR-responsive cancer phenotypes in patients with CRC and melanoma; and on how to investigate and interpret the prometastatic infrastructure in the real pathophysiological context of patients with cancer undergoing surgical procedures and receiving pharmacological treatments with multiple side effects, including those affecting the LPR, its stimulating factors and responsive cancer phenotypes.

Tumor cell-released LC3-positive EVs promote lung metastasis of breast cancer through enhancing premetastatic niche formation.

Most breast cancer-related deaths are caused by metastasis in vital organs including the lungs. Development of supportive metastatic microenvironments, referred to as premetastatic niches (PMNs), in certain distant organs before arrival of metastatic cells, is critical in metastasis. However, the mechanisms of PMN formation are not fully clear. Here, we demonstrated that chemoattractant C-C motif chemokine ligand 2 (CCL2) could be stimulated by heat shock protein 60 (HSP60) on the surface of murine 4 T1 breast cancer cell-released LC3+ extracellular vesicles (LC3+ EVs) via the TLR2-MyD88-NF-κB signal cascade in lung fibroblasts, which subsequently promoted lung PMN formation through recruiting monocytes and suppressing T cell function. Consistently, reduction of LC3+ EV release or HSP60 level or neutralization of CCL2 markedly attenuated PMN formation and lung metastasis. Furthermore, the number of circulating LC3+ EVs and HSP60 level on LC3+ EVs in the plasma of breast cancer patients were positively correlated with disease progression and lung metastasis, which might have potential value as biomarkers of lung metastasis in breast cancer patients (AUC = 0.898, 0.694, respectively). These findings illuminate a novel mechanism of PMN formation and might provide therapeutic targets for anti-metastasis therapy for patients with breast cancer.

Targeting complement-mediated immunoregulation for cancer immunotherapy.

Complement was initially discovered as an assembly of plasma proteins "complementing" the cytolytic activity of antibodies. However, our current knowledge places this complex system of several plasma proteins, receptors, and regulators in the center of innate immunity as a bridge between the initial innate responses and adaptive immune reactions. Consequently, complement appears to be pivotal for elimination of pathogens, not only as an early response defense, but by directing the subsequent adaptive immune response. The discovery of functional intracellular complement and its roles in cellular metabolism opened novel avenues for research and potential therapeutic implications. The recent studies demonstrating immunoregulatory functions of complement in the tumor microenvironment and the premetastatic niche shifted the paradigm on our understanding of functions of the complement system in regulating immunity. Several complement proteins, through their interaction with cells in the tumor microenvironment and in metastasis-targeted organs, contribute to modulating tumor growth, antitumor immunity, angiogenesis, and therefore, the overall progression of malignancy and, perhaps, responsiveness of cancer to different therapies. Here, we focus on recent progress in our understanding of immunostimulatory vs. immunoregulatory functions of complement and potential applications of these findings to the design of novel therapies for cancer patients.

Twelfth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer.

The twelfth annual workshop of the European Network for Breast Development and Cancer focused on methods in mammary gland biology and breast cancer, was scheduled to take place on March 26-28, 2020, in Weggis, Switzerland. Due to the COVID-19 pandemic, the meeting was rescheduled twice and eventually happened as a virtual meeting on April 22 and 23, 2021. The main topics of the meeting were branching and development of the mammary gland, tumor microenvironment, circulating tumor cells, tumor dormancy and breast cancer metastasis. Novel and unpublished findings related to these topics were presented, with a particular focus on the methods used to obtain them. Virtual poster sessions were a success, with many constructive and fruitful interactions between researchers and covered many areas of mammary gland biology and breast cancer.

Inhalable Porous Microspheres Loaded with Metformin and Docosahexaenoic Acid Suppress Tumor Metastasis by Modulating Premetastatic Niche.

Cancer metastasis is the major cause of cancer-related death; therefore, achieving suppression of tumor metastasis is a long-sought goal in cancer therapy. As the premetastatic niche acts as a prerequisite for tumor metastasis, it serves as an effective target for metastasis suppression. This study tests the feasibility of inhalable porous microspheres loaded with two premetastatic niche modulation agents, metformin and docosahexaenoic acid, as orthotopic delivery carriers for the reversion of lung premetastatic microenvironments and targeted suppression of tumor lung metastasis. The microspheres were prepared via an improved emulsion-solvent evaporation method and exhibit an excellent lung deposition, leading to significant inhibition of circulating tumor cells (CTCs)-endothelial cells adhesion, reduction of vascular permeability, and suppression of adhesion protein expression in lung premetastatic microenvironments. As a result, inhalable microspheres can prevent tumor lung metastasis formation excellently in vivo. Overall, this study proved that the encapsulation of metformin and docosahexaenoic acid in inhalable microspheres could be a promising strategy for tumor lung metastasis inhibition via orthotopically modulating premetastatic niche in the lungs.

Organ tropism in solid tumor metastasis: an updated review.

Tumors are equipped with a highly complex machinery of interrelated events so as to adapt to hazardous conditions, preserve a growing cell mass and thrive at the site of metastasis. Tumor cells display metastatic propensity toward specific organs where the stromal milieu is appropriate for their further colonization. Effective colonization relies on the plasticity of tumor cells in adapting to the conditions of the new area by reshaping their epigenetic landscape. Breast cancer cells, for instance, are able to adopt brain-like or epithelial/osteoid features in order to pursue effective metastasis into brain and bone, respectively. The aim of this review is to discuss recent insights into organ tropism in tumor metastasis, outlining potential strategies to address this driver of tumor aggressiveness.

Self-Delivery Micellar Nanoparticles Prevent Premetastatic Niche Formation by Interfering with the Early Recruitment and Vascular Destruction of Granulocytic Myeloid-Derived Suppressor Cells.

Distal metastases of tumors result from the interaction between "seeds" (circulating tumor cells, CTCs) and "soil" (premetastatic niche, PMN). Various strategies focus on CTC inhibition, but only a few strategies inhibit PMN formation. The main predisposition of PMN formation in melanoma lies in the pulmonary recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11b+Ly6G+ cells) induced by tumors, which increase vascular permeability by secreting matrix metalloproteinase-9 (MMP-9) and result in immunosuppression by secreting interleukin-10 (IL-10) in premetastatic lungs. Here, a micellar hypotoxic low molecular weight heparin-tocopherol succinate nanoparticle (LMWH-TOS nanoparticle, LT NP) was established and investigated for its influence on PMN formation in this study. We first demonstrated that the hydrophilic segment LMWH in LT NPs can inhibit early pulmonary recruitment of G-MDSCs through interrupting their extravasation by inhibiting P-selectin/PSGL-1-mediated adhesion between vascular endothelial cells and G-MDSCs. In addition, the hydrophobic segment (TOS) in LT NPs significantly inhibited the expression of MMP-9 in G-MDSCs. As a result, the drug-free nanoparticles could maintain the normal microenvironment of lungs, thus effectively inhibiting implantation and colonization of CTCs. Further, phenylboronic acid (PBA)-modified and doxorubicin/immunopotentiator α-galactosylceramide (αGC)-coloaded nanoparticles (PLT/DOX/αGC NPs) were exploited. PBA modification achieved targeted chemotherapy by binding to overexpressed sialic acid residues on the tumor cell surface. This nanosystem effectively inhibited the postoperative metastasis and tumor recurrence simultaneously. Our work provides a proof of concept that the prevention of PMN formation through interfering G-MDSCs with self-delivery nanosystems is a safe and effective antimetastasis strategy.

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression.

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

How to Target Spinal Metastasis in Experimental Research: An Overview of Currently Used Experimental Mouse Models and Future Prospects.

The spine is one of the organs that is most affected by metastasis in cancer patients. Since the control of primary tumor is continuously improving, treatment of metastases is becoming one of the major challenges to prevent cancer-related death. Due to the anatomical proximity to the spinal cord, local spread of metastasis can directly cause neurological deficits, severely limiting the patient's quality of life. To investigate the underlying mechanisms and to develop new therapies, preclinical models are required which represent the complexity of the multistep cascade of metastasis. Current research of metastasis focuses on the formation of the premetastatic niche, tumor cell dormancy and the influence and regulating function of the immune system. To unveil whether these influence the organotropism to the spine, spinal models are irreplaceable. Mouse models are one of the most suitable models in oncologic research. Therefore, this review provides an overview of currently used mouse models of spinal metastasis. Furthermore, it discusses technical aspects clarifying to what extend these models can picture key steps of the metastatic process. Finally, it addresses proposals to develop better mouse models in the future and could serve as both basis and stimulus for researchers and clinicians working in this field.