Pre-metastatic Niche Research Articles

Isolated Pancreatic Metastases of Renal Cell Carcinoma-Clinical Particularities and Seed and Soil Hypothesis.

A meta-analysis of 1470 isolated pancreatic metastases of renal cell carcinoma revealed, that, in addition to the unusual exclusive occurrence of pancreatic metastases and the favourable treatment results, the isPMRCC is characterised by further peculiarities of the clinical course: The lack of prognostic significance of volume and growth rate dependent risk factors and the independence of treatment results from standard or local resections. As an explanation for all these peculiarities, according to today's knowledge, a strong acting seed and soil mechanism can serve, which allows embolized tumour cells to grow to metastases only in the pancreas, and prevents them definitively or for years in all other organs. The good prognosis affects not only isolated PM, but also multi-organ metastases of the RCC, in which the additional occurrence of PM is also associated with a better prognosis. Genetic studies revealed specific changes in cases of PM of RCC: Lack of loss of 9p21.3 and 14q31.2, which are otherwise specific gene mutations at the onset of generalization, a low weight genome instability index, i.e., high genetic stability, and a low rate of PAB1 and a high rate of BPRM1 alterations, which signal a more favourable course. The cause of pancreatic organotropism in isPMRCC is still unclear, so only those factors that have been identified as promoting organotropism in other, more frequent tumour entities can be presented: Formation of the pre-metastatic niche, chemokine receptor-ligand mechanism, ability to metabolic adaptation, and immune surveillance.

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy.

Extracellular vesicles (EVs) are a heterogeneous group of cell-secreted particles that carry cargo of functional biomolecules crucial for cell-to-cell communication with both physiological and pathophysiological consequences. In this review, we focus on evidence demonstrating that the EV-mediated crosstalk between melanoma cells within tumor, between melanoma cells and immune and stromal cells, promotes immune evasion and influences all steps of melanoma development from local progression, pre-metastatic niche formation, to metastatic colonization of distant organs. We also discuss the role of EVs in the development of resistance to immunotherapy and therapy with BRAFV600/MEK inhibitors, and shortly summarize the recent advances on the potential applications of EVs in melanoma diagnostics and therapy.

Capsaicin shapes gut microbiota and pre-metastatic niche to facilitate cancer metastasis to liver

Dietary factors are fundamental in tumorigenesis throughout our lifetime. A spicy diet has been ambiguous on the development of cancers, especially in the study of colon cancer metastasis. Here, we utilized a mouse metastasis model to test the potential role of capsaicin in influencing metastasis. Long-term continuous administration of capsaicin diet (300 mg/kg) to mice promotes the formation of liver pre-metastatic niche to facilitate the metastasis of colon cancer cells. Bacteria translocation to liver is clearly observed. Capsaicin increases intestinal barrier permeability and disrupts gut vascular barrier by altering the composition of gut microbiota. Capsaicin not only changes the abundance of mucin-related bacteria like Akkermanisa and Muribaculaceae, but also bacteria involved in bile acids metabolism. Dysregulated bile acids profile is related to the recruitment of natural killer T (NKT) cells in pre-metastatic niche, primary bile acid α-Muricholic acid can enhance the recruitment of NKT cells, while secondary bile acids Glycoursodeoxycholic acid and Taurohyodeoxycholic acid impair the recruitment of NKT cells. These findings reveal long term consumption of capsaicin increases the risk of cancer metastasis through modulating the gut microbiota. Capsaicin (300 mg/kg) disrupts gut barrier and promotes the translocation of bacteria to liver, while altered bile acids metabolism affects the recruitment of NKT cells in liver, forming a pre-metastatic niche and promoting cancer metastasis.

Inhibitory Effect of Astragalus Polysaccharide on Premetastatic Niche of Lung Cancer through the S1PR1-STAT3 Signaling Pathway.

As a common malignant tumor, the morbidity and mortality of lung cancer have been rising in recent years. The concept of "premetastatic niche" may lead to a revolutionary change in antitumor metastasis therapeutic strategies. Traditional Chinese medicine with multitargets and lower poisonous agents may be a potentially effective means to intervene in the "premetastatic niche (PMN)" to prevent and treat tumor metastasis. Astragalus polysaccharide (APS) is a substance with strong immune activity in Astragalus membranaceus that has excellent biological activities such as immunomodulation, anti-inflammatory, and antitumor. In this study, we constructed a tumor lung metastasis animal model to explore the intervention mechanism of APS on the premetastatic niche. We found that APS inhibited the formation of the lung premetastatic niche and inhibited the recruitment of myeloid-derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and gene expression of S1PR1, STAT3, and p-STAT3 in the S1PR1/STAT3 signaling pathway were suppressed by APS. In line with the above findings, our results confirmed that APS may inhibit the accumulation of MDSCs in the premetastatic niche through the intervention of the S1PR1-STAT3 signaling pathway to achieve the antitumor effect.

Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer.

Rationale: Breast cancer (BC), as one of the most frequently diagnosed cancer, has a poor prognosis due to the development of distant metastasis. Among the BC metastatic sites, lung is one of the most common sites. Caveolin-1 (Cav-1) is a functional membrane protein that plays a vital role in tumor metastasis. Although studies have revealed that Cav-1 levels were elevated in patients with advanced cancer, whether Cav-1 affects BC lung metastasis by influencing the formation of pre-metastatic niche (PMN) through exosomes has not been explored. Methods: Differential ultracentrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to verify the presence of exosomes. Transwell assays were used to examine the biological effects of exosomes containing Cav-1. Both in vitro cell cultures and mammary tumor cell-induced mouse models were used to assess the lung metastasis. The regulatory mechanisms of PMN formation were revealed using western blot, flow cytometry, RT-qPCR, immunofluorescence assays, gene overexpression assays and RNA interference assays. Results: Exosomes have critical functions in transporting Cav-1 between primary BC and metastatic organ microenvironments. Cav-1 in BC-derived exosomes can act as a signaling molecule to mediate intercellular communication and regulate the PMN before lung metastasis by regulating the expression of PMN marker genes and inflammatory chemokines in lung epithelial cells, promoting the secretion of tenascin-C (TnC) in lung fibroblasts to cause extracellular matrix (ECM) deposition, and inhibiting the PTEN/CCL2/VEGF-A signaling pathway in lung macrophages to facilitate their M2-type polarization and angiogenesis. Conclusion: Our study investigated the mechanisms of lung PMN formation induced by Cav-1 in BC-derived exosomes. Our data may provide new directions for exploring the mechanisms and developing treatment strategies of BC lung metastasis.

Pre-metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis.

Breast cancer (BC) is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths in women worldwide. Metastasis is a major contributor to high cancer mortality and is usually the endpoint of a series of sequential and dynamic events. One of the critical events is forming a pre-metastatic niche (PMN) that occurs before macroscopic tumor cell invasion and provides a suitable environment for tumor cells to colonize and progress into metastases. Due to the unique characteristics of PMN in cancer metastasis, developing therapies to target PMN may bring new advantages in preventing cancer metastasis at an early stage. Various biological molecules, cells, and signaling pathways are altered in BC, regulating the functions of distinctive immune cells and stromal remodeling, inducing angiogenesis, and effect metabolic reprogramming and organotropism to promote PMN formation. In this review, we elucidate the multifaceted mechanisms contributing to the development of PMN in BC, discuss the characteristics of PMN, and highlight the significance of PMN in providing potential diagnostic and therapeutic strategies for BC metastasis, which may bring promising insights and foundations for future studies.

Tagging the pre-metastatic node in oral cancer: A cross-sectional study.

Lymph node involvement is the first indication of spread of oral squamous cell carcinoma (OSCC) and it is also a most significant prognostic factor. Lymph nodes show various tumor-induced histological changes preceding actual metastasis, viz. increased vascularity, follicular hyperplasia and desmoplasia which leads to pre-metastatic niche formation. This pre-metastatic niche primarily provides a favorable microenvironment to for the survival and subsequent growth of cancer cells within the lymph node. A retrospective study to evaluate carcinoma-induced changes in lymph nodes harvested from radical neck dissection in OSCC patients. 1) To evaluate cancer-induced histological changes in positive and negative lymph nodes in OSCC patients. 2) To look for common histopathological changes in both pre-metastatic and metastatic lymph nodes. Forty lymph nodes harvested from seven OSCC patients were sectioned and stained (Hematoxylin-Eosin) for documentation of histologically evident morphological and functional alterations. The Chi-square test was applied between the non-metastatic and metastatic lymph nodes findings and a statistically significant difference was seen. Sections from 28 negative nodes showed changes associated with pre-metastatic niche conditioning whereas, 12 sections exhibit frank metastases. The modified immunological responses and remodeling of the vasculature are the most common histologic tumor-induced pre-metastatic changes. This study reviewed and categorized these histological changes that point to pre-metastatic niche conditioning of lymph nodes.

Xiaoliu Pingyi Pecipe Inhibits Lung Pre-Metastatic Niche Formation and Prevents Myeloid-Derived Suppressor Cells Recruitment.

Metastasis, a leading cause of cancer-related deaths, involves complex mechanisms. The premetastatic niche (PMN) is a crucial contributor to this process. Myeloid-derived suppressor cells (MDSCs) play an important role in PMN formation and promote tumor progression and metastasis. The Xiaoliu Pingyi recipe (XLPYR), a traditional Chinese medicine, is effective in preventing postoperative recurrence and metastasis in cancer patients. This study investigated the effects of XLPYR on MDSCs recruitment and on the expression of PMN markers and elucidated the mechanisms involved in the prevention of tumor metastasis. C57BL/6 mice were subcutaneously injected with Lewis cells and treated with cisplatin and XLPYR. Tumors were resected after 14 days after the establishment of a model of lung metastasis, and tumor volume and weight were measured. Lung metastases were observed 21 days after resection. MDSCs in the lung, spleen, and peripheral blood were detected by flow cytometry. Western blotting, qRT-PCR and ELISA were used to detect the expression of S100A8, S100A9, MMP9, LOX, and IL-6/STAT3 in premetastatic lung tissue. XLPYR treatment inhibited tumor growth and prevented lung metastasis. Compared to mice without subcutaneous tumor cell transplantation, the model group had an increased proportion of MDSCs, higher expression of S100A8, S100A9, MMP9, and LOX in the premetastatic lung. XLPYR treatment reduced the proportion of MDSCs, S100A8, S100A9, MMP9, and LOX expression, and downregulated the IL-6/STAT3 pathway. XLPYR may prevent MDSCs recruitment and reduce the expression of S100A8, MMP9, LOX, and IL6/STAT3 in premetastatic lung tissue, thus reducing lung metastases.

Exosomes-mediated tumor metastasis through reshaping tumor microenvironment and distant niche.

Tumor-derived exosomes (TDEs) are the particular communicator and messenger between tumor cells and other cells containing cancer-associated genetic materials and proteins. And TDEs who are also one of the important components consisting of the tumor microenvironment (TME) can reshape and interact with TME to promote tumor development and metastasis. Moreover, due to their long-distance transmission by body fluids, TDEs can facilitate the formation of pre-metastatic niche to support tumor colonization. We discuss the main characteristics and mechanism of TDE-mediated tumor metastasis by reshaping TME and pre-metastatic niche as well as the potential of TDEs for diagnosing tumor and predicting future metastatic development.

Hypoxia-induced exosomes facilitate lung pre-metastatic niche formation in hepatocellular carcinoma through the miR-4508-RFX1-IL17A-p38 MAPK-NF-κB pathway.

Background: Hypoxia plays an important role in the lung metastasis of hepatocellular carcinoma (HCC). However, the process by which hypoxia promotes the formation of a pre-metastatic niche (PMN) and its underlying mechanism remain unclear. Methods: Exosomes derived from normoxic and hypoxic HCC cells were collected to induce fibroblast activation in vitro and PMN formation in vivo. The micro RNA (miR) profiles of the exosomes were sequenced to identify differentially expressed miRNAs. Gain- and loss-of-function analyses were performed to investigate miR-4508 function. Dual-luciferase, western blotting, and real-time reverse transcription-PCR analyses were used to identify the direct targets of miR-4508 and its downstream signaling pathways. To demonstrate the roles of hypoxic tumor-derived exosomes (H-TDEs) and miR-4508 in the lung metastasis of liver cancer, H22 tumor cells were injected through the tail vein of mice. Blood plasma-derived exosomes from patients with HCC who underwent transarterial chemoembolization (TACE) were applied to determine clinical correlations. Results: We demonstrated that H-TDEs activated lung fibroblasts and facilitated PMN formation, thereby promoting lung metastasis in mice. Screening for upregulated exosomal miRNAs revealed that miR-4508 and its target, regulatory factor X1 (RFX1), were involved in H-TDE-induced lung PMN formation. Moreover, miR-4508 was significantly upregulated in plasma exosomes derived from patients with HCC after TACE. We confirmed that the p38 MAPK-NF-κB signaling pathway is involved in RFX1 knockdown-induced fibroblast activation and PMN formation. In addition, IL17A, a downstream target of RFX1, was identified as a link between RFX1 knockdown and p38 MAPK activation in fibroblasts. Conclusion: Hypoxia enhances the release of TDEs enriched with miR-4508, thereby promoting lung PMN formation by targeting the RFX1-IL17A-p38 MAPK-NF-κB pathway. These findings highlight a novel mechanism underlying hypoxia-induced pulmonary metastasis of HCC.

Retracted: Breast Cancer Cells Metastasize to the Tissue‐Engineered Premetastatic Niche by Using an Osteoid‐Formed Polycaprolactone/Nanohydroxyapatite Scaffold

Retracted: Breast Cancer Cells Metastasize to the Tissue‐Engineered Premetastatic Niche by Using an Osteoid‐Formed Polycaprolactone/Nanohydroxyapatite Scaffold

Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients.

Breast cancer is the predominant form of carcinoma among women worldwide, with 70% of advanced patients developing bone metastases, with a high mortality rate. In this sense, the bone marrow (BM) mesenchymal stem/stromal cells (MSCs) are critical for BM/bone homeostasis, and failures in their functionality, transform the BM into a pre-metastatic niche (PMN). We previously found that BM-MSCs from advanced breast cancer patients (BCPs, infiltrative ductal carcinoma, stage III-B) have an abnormal profile. This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients. A comparative analysis was undertaken, which included self-renewal capacity, morphology, proliferation capacity, cell cycle, reactive oxygen species (ROS) levels, and senescence-associated β‑galactosidase (SA‑β‑gal) staining of BM-derived MSCs isolated from 14 BCPs and 9 healthy volunteers (HVs). Additionally, the expression and activity of the telomerase subunit TERT, as well as telomere length, were measured. Expression levels of pluripotency, osteogenic, and osteoclastogenic genes (OCT-4, SOX-2, M-CAM, RUNX-2, BMP-2, CCL-2, M-CSF, and IL-6) were also determined. The results showed that MSCs from BCPs had reduced ,self-renewal and proliferation capacity. These cells also exhibited inhibited cell cycle progression and phenotypic changes, such as an enlarged and flattened appearance. Additionally, there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length. We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression. We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

Extracellular vesicles and particles as mediators of long-range communication in cancer: connecting biological function to clinical applications.

Over the past decade, extracellular vesicles and particles (EVPs) have emerged as critical mediators of intercellular communication, participating in numerous physiological and pathological processes. In the context of cancer, EVPs exert local effects, such as increased invasiveness, motility, and reprogramming of tumor stroma, as well as systemic effects, including pre-metastatic niche formation, determining organotropism, promoting metastasis and altering the homeostasis of various organs and systems, such as the liver, muscle, and circulatory system. This review provides an overview of the critical advances in EVP research during the past decade, highlighting the heterogeneity of EVPs, their roles in intercellular communication, cancer progression, and metastasis. Moreover, the clinical potential of systemic EVPs as useful cancer biomarkers and therapeutic agents is explored. Last but not least, the progress in EVP analysis technologies that have facilitated these discoveries is discussed, which may further propel EVP research in the future.

Neoplasms – biological phenomenon

Neoplasm is the cause of a double disease of the body, i.e. with two faces (Janus disease), which means both the presence of cancer cells and the secondary disorders of the immune system function caused by them. The second possibility is a temporary decrease in immunity, caused by e.g. influenza, and revealing a neoplastic disease. Neoplasms are induced by both genetic and epigenetic factors (Fig. 1), giving different types of mono- and polyclonal metastases and cross-spreading (Fig. 2). Recently, exosomes have been ascribed an important role in the formation of metastases. They transfer information between normal and cancer cells by horizontal transfer and „teach” myeloid cells to move to the pre-metastatic niche and the metastatic deposit. In carcinogenesis, the main role is played by long-lived cancer stem cells, as well as differentiated cells after they have gained the ability to self-renew, as in stem cells. The paper also presents examples of neoplasms accompanied by a second, primary neoplasm in the same system or in the vicinity. Multiple primary malignances (MPM) associated with them have also been described. With the help of the so-called strange attractor, an attempt was made to describe the behavior of cancers in connection with the phenomenon of deterministic chaos based on the process of entropy. Distinguishing between chaotic and stochastic (random) systems is very difficult in biology.

Global Trends and Prospects Regarding Exosomes in Cancer Immunology Research Over the Past 10 Years.

Background: Exosomes and cancer immunology are both important areas of research for cancer treatment. As much effort has been made to explore the relationship between exosomes and cancer immunology, exosomes in cancer immunology have become a hotspot in medical research. Methods: We retrieved all relevant publications between 2011 and 2021 from the Web of Science and utilized Microsoft Excel 365, Citespace, Online Analysis Platform of Literature Metrology (http://bibliometric.com/) and software including VOS viewer to analyze and visualize the research result. Results: Of the 820 studies included, China published the most articles, followed by the USA. Cooperation between countries has progressed over the past decade. Shanghai Jiao Tong University and Oncotargets and Therapy were the institution and journal that published the most articles respectively. The most frequently cited article in this field, titled "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver," was published in Nature Cell Biology. Keywords were divided into three: Mechanism research, treatment application research, and diagnosis and prognosis research of which the latter was the newest cluster. "Microenvironment," "PD-L1" and "M2 macrophage" were representative new keywords while "tumor suppressor" was the keyword cited most frequently. Conclusion: The publication trend shows that cooperation between different countries and institutions contributes to the development of this field. Researchers should continue to extend collaborations for further advances. The rising relative research interest indicated that this is a hot topic with great research potential. Macrophages polarization and PD-L1 application in tumor immunotherapy are worthy of further research. Hotspots will likely transfer from mechanistic research to clinical research, particularly for methods to increase the survival rate and improve the prognosis of cancer patients.

Analysis of tumor-draining vein secretome: A direct access to tumor-derived extracellular vesicles in surgical lung cancer patients

Tumor-secreted extracellular vesicles (EVs) participate in the metastasis process through different mechanisms, including the preparation of the pre-metastatic niche to grant circulating tumor cells (CTCs) implantation and growth. The study of the metastasis process through the analysis of CTCs and tumor-derived EVs is difficult because of the dilution grade of these elements in peripheral blood. In early-stage lung cancer patients, the tumor-secreted products are even more diluted. An attractive strategy in surgical lung cancer patients is to purify them from a pulmonary tumor-draining vein where they are enriched. The information obtained from the analysis of EVs and CTCs purified from this source could give more accurate information about tumor biology and could be an important source of biomarkers to identify patients at high risk of relapse after curative surgery.

MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential.

Bone is a frequent site of metastasis. Bone metastasis is associated with a short-term prognosis in cancer patients, and current treatments aim to slow its growth, but are rarely curative. Thus, revealing molecular mechanisms that explain why metastatic cells are attracted to the bone micro-environment, and how they successfully settle in the bone marrow-taking advantage over bone resident cells-and grow into macro-metastasis, is essential to propose new therapeutic approaches. MicroRNAs and snoRNAs are two classes of small non-coding RNAs that post-transcriptionally regulate gene expression. Recently, microRNAs and snoRNAs have been pointed out as important players in bone metastasis by (i) preparing the pre-metastatic niche, directly and indirectly affecting the activities of osteoclasts and osteoblasts, (ii) promoting metastatic properties within cancer cells, and (iii) acting as mediators within cells to support cancer cell growth in bone. This review aims to highlight the importance of microRNAs and snoRNAs in metastasis, specifically in bone, and how their roles can be linked together. We then discuss how microRNAs and snoRNAs are secreted by cancer cells and be found as extracellular vesicle cargo. Finally, we provide evidence of how microRNAs and snoRNAs can be potential therapeutic targets, at least in pre-clinical settings, and how their detection in liquid biopsies can be a useful diagnostic and/or prognostic biomarker to predict the risk of relapse in cancer patients.

Single-Cell Transcriptomic Profiles of Lung Pre-Metastatic Niche Reveal Neutrophil and Lymphatic Endothelial Cell Roles in Breast Cancer

The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of N2-type neutrophils and classical monocytes associated with chronic inflammation; notably, lung neutrophils isolated from mice with primary cancer exhibited similar N2-type phenotypes and expressed high levels of inflammatory and angiogenic factors. We also discovered a new cluster of Ki67-upregulated lymphatic endothelial cells (ECs) that activated several cell division-related pathways. Receptor-ligand interactions within the lung potentially mediated PMN formation; these were exemplified by the cross talk of lymphatic EC-N2-type neutrophil via S100A6. In vitro study revealed S100A6 impaired EC tight junction and increased the transendothelial migration of neutrophils. Our results highlight the molecular mechanisms that shape lung PMN and inspire preventive strategies for lung metastasis in breast cancer.

Current Status of Research on Small Extracellular Vesicles for the Diagnosis and Treatment of Urological Tumors

Extracellular vesicles (EVs) are important mediators of communication between tumor cells and normal cells. These vesicles are rich in a variety of contents such as RNA, DNA, and proteins, and can be involved in angiogenesis, epithelial-mesenchymal transition, the formation of pre-metastatic ecological niches, and the regulation of the tumor microenvironment. Small extracellular vesicles (sEVs) are a type of EVs. Currently, the main treatments for urological tumors are surgery, radiotherapy, and targeted therapy. However, urological tumors are difficult to diagnose and treat due to their high metastatic rate, tendency to develop drug resistance, and the low sensitivity of liquid biopsies. Numerous studies have shown that sEVs offer novel therapeutic options for tumor treatment, such as tumor vaccines and tumor drug carriers. sEVs have attracted a great deal of attention owing to their contribution to in intercellular communication, and as novel biomarkers, and role in the treatment of urological tumors. This article reviews the research and applications of sEVs in the diagnosis and treatment of urological tumors.

Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer.

Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.