Pre-metastatic Niche Formation Research Articles

Emerging Roles of Small Extracellular Vesicles in Gastrointestinal Cancer Research and Therapy

Discovered in the late eighties, sEVs are small extracellular nanovesicles (30–150 nm diameter) that gained increasing attention due to their profound roles in cancer, immunology, and therapeutic approaches. They were initially described as cellular waste bins; however, in recent years, sEVs have become known as important mediators of intercellular communication. They are secreted from cells in substantial amounts and exert their influence on recipient cells by signaling through cell surface receptors or transferring cargos, such as proteins, RNAs, miRNAs, or lipids. A key role of sEVs in cancer is immune modulation, as well as pro-invasive signaling and formation of pre-metastatic niches. sEVs are ideal biomarker platforms, and can be engineered as drug carriers or anti-cancer vaccines. Thus, sEVs further provide novel avenues for cancer diagnosis and treatment. This review will focus on the role of sEVs in GI-oncology and delineate their functions in cancer progression, diagnosis, and therapeutic use.

Abstract C031: Differential growth of pancreatic ductal adenocarcinoma cells in serum amyloid A (SAA) deficient mouse model through immune modulation

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge to cure and expected to be the second leading cause of cancer-related deaths in the US by 2030. Its aggressive nature stems from late diagnosis and early metastasis. PDAC cells interact with the host system and impair the immune response. This communication leads to the production of mediators by host cells, creating an environment that supports PDAC cells growth and the formation of premetastatic niches. Despite progress, the specific factors and mechanisms underlying immune modulation in PDAC progression are not fully understood. Methods: PDAC mice models (WT-KPCL and KOSAA-KPCL) were developed by administering luciferase-expressing KPC cells (KPCL) intraperitoneally into eight weeks old male C57BL/6 mice. The control groups (WT and KOSAA) received PBS. Plasma proteomics was analyzed by using Mass Spectrometry (MS). PDAC cells growth was visualized by bioluminescence using Lago X in-vivo imaging system. Results: During tumor progression, KPCL mice exhibited significant weight loss, with the loss of adipose tissue and skeletal muscle, indicating a hallmark of pancreatic cancer. To identify potential circulating molecules involved in tumor progression, we conducted proteomics analysis on plasma samples using MS. Comparative analysis revealed that out of 734 circulating proteins, 86 were upregulated and 35 were downregulated in tumor mice compared to controls. Serum Amyloid A 1 and 2 were found to be the most abundantly expressed proteins in the plasma of tumor mice, with a remarkable 1024-fold increase compared to controls. To determine the major source of SAA in tumor mice, we measured SAA1, 2, and 3 expressions in various tissues, including adipose tissue, liver, muscle, and tumor. Interestingly, adipose tissue displayed a substantial contribution to SAA levels in WT-KPCL. However, we were unable to detect SAA expression in the tumor tissue from KOSAA-KPCL indicating negligible source of SAA from KPCL cells. Intrigued by these findings, we studied the role of SAA in PDAC cell proliferation in-vivo. Luciferase-expressing KPC cells were injected into SAA-KO mice (KOSAA-KPCL) and controls (WT-KPCL). Unexpectedly, bioluminescence imaging revealed a dramatic growth of KPC cells in the pancreas of SAA-deficient animals. This was supported by a significantly higher rate of metastasis to the liver, increased by 62.5% in KOSAA-KPCL compared to WT-KPCL. SAA is retinol-binding protein and retinoic acid plays a vital role in the immune system. We found a decreased concentration of retinoic acid in the plasma of KOSAA-KPCL mice, with a significant decrease in CD8 expression in tumor tissue isolated from KOSAA-KPCL. These results suggest that SAA modulates immune response during PDAC cells growth. Conclusion: Our study demonstrates that adipose tissue is likely a major source of SAA, where the absence of SAA leads to enhanced PDAC cells growth and metastasis through immune modulation. These findings suggest the therapeutic potential of SAA for pancreatic cancer. Citation Format: Yuki Takamuku, Mengistu Lemecha, Keiichi Itakura. Differential growth of pancreatic ductal adenocarcinoma cells in serum amyloid A (SAA) deficient mouse model through immune modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C031.

Tumor-Derived RAB21+ABHD12+ sEVs Drive the Premetastatic Microenvironment in the Lung.

Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the notable characteristics in the premetastatic niche, which is a fundamental requirement for primary tumor metastasis. Here, we demonstrated that small extracellular vesicles (sEV) carrying RAB21 homed to lung macrophages and interacted with integrin-β1 on macrophages. ABHD12 expression was high in lung metastatic tumors and was mostly expressed by macrophages. Head and neck squamous cell carcinoma (HNSCC)-derived sEVs carrying ABHD12-polarized macrophages toward an immunosuppressive phenotype, driving premetastatic niche formation, which facilitated lung metastasis. ABHD12 additionally upregulated S1PR1 by activating the AKT-FoxO1 pathway in macrophages, and significantly enhanced antitumor responses were observed in tumor models treated with agents targeting both S1PR1 and PD-1. Collectively, our study suggests that RAB21+ABHD12+ sEVs derived from HNSCC cells contribute to the formation of the immunosuppressive microenvironment in the premetastatic niche and are a potential therapeutic target for enhancing the antitumor efficacy of anti-PD-1 therapy.

The Role of Osteocytes in Pre-metastatic Niche Formation.

The formation of a pre-metastatic niche (PMN), in which primary cancer cells prime the distant site to be favorable to their engraftment and survival, may help explain the strong osteotropism observed in multiple cancers, such as breast and prostate. PMN formation, which includes extracellular matrix remodeling, increased angiogenesis and vascular permeability, enhanced bone marrow-derived cell recruitment and immune suppression, has mostly been described in soft tissues. In this review, we summarize current literature of PMN formation in bone. We also present evidence of a potential role for osteocytes to be the primary mediators of PMN development. Osteocytes regulate the bone microenvironment in myriad ways beyond canonical bone tissue remodeling, including changes that contribute to PMN formation. Perilacunar tissue remodeling, which has been observed in both bone and non-bone metastatic cancers, is a potential mechanism by which osteocyte-cancer cell signaling stimulates changes to the bone microenvironment. Osteocytes also protect against endothelial permeability, including that induced by cancer cells, in a loading-mediated process. Finally, osteocytes are potent regulators of cells within the bone marrow, including progenitors and immune cells, and might be involved in this aspect of PMN formation. Osteocytes should be examined for their role in PMN formation.

Retracted: Noncoding RNAs Act as Tumor-Derived Molecular Components in Inducing Premetastatic Niche Formation.

[This retracts the article DOI: 10.1155/2019/9258075.].

Fibroblasts: invigorated targets in pre-metastatic niche formation.

At present, tumor metastasis still remains the leading contributor to high recurrence and mortality in cancer patients. There have been no clinically effective therapeutic strategies for treating patients with metastatic cancer. In recent years, a growing body of evidence has shown that the pre-metastatic niche (PMN) plays a crucial role in driving tumor metastasis. Nevertheless, a clear and detailed understanding of the formation of PMN is still lacking given the fact that PMN formation involves in a wealth of complicated communications and underlying mechanisms between primary tumors and metastatic target organs. Despite that the roles of numerous components including tumor exosomes and extracellular vesicles in influencing the evolution of PMN have been well documented, the involvement of cancer-associated fibroblasts (CAFs) in the tumor microenvironment for controlling PMN formation is frequently overlooked. It has been increasingly recognized that fibroblasts trigger the formation of PMN by virtue of modulating exosomes, metabolism and so on. In this review, we mainly summarize the underlying mechanisms of fibroblasts from diverse origins in exerting impacts on PMN evolution, and further highlight the prospective strategies for targeting fibroblasts to prevent PMN formation.

Participation of suicide gene extracellular vesicles in metastasis prevention.

The incidence of distant metastases is associated with most cancer-related mortalities. Extracellular vesicles (EVs), secreted from tumors and cancer-associated fibroblasts, are involved in the metastatic process mediating their organotropism through their involvement in the pre-metastatic niche formation. We have been developing suicide gene therapy mediated by EVs secreted from mesenchymal stem/ stromal cells, tumor cells, and cancer-associated fibroblasts. Suicide gene EVs conjugated with prodrug are tumor tropic, penetrate tumor cells, and kill them by intracellular conversion of nontoxic prodrug to an efficient anti-cancer drug. Here, we discuss findings regarding the possibility of using suicide gene EVs as a novel therapeutic approach for metastases, via pre-metastatic niche modification. The suicide gene EVs provide a future perspective for metastasis prevention.

Capsaicin and Cold exposure promote EMT-mediated premetastatic niche formation to facilitate colorectal cancer metastasis.

Colorectal cancer (CRC) is a common malignant tumor worldwide. Capsaicin and cold exposure were positively correlated with CRC metastasis. However, the mechanisms of action underlying capsaicin and cold exposure in 1,2-dimethylhyrazine (DMH)-induced CRC remain unknown. Multiple assays were utilized in the present study, including methylene blue, hematoxylin eosin (H&E) and immunohistochemistry (IHC) staining, western blotting and Duolink proximity ligation assay (PLA), in order to assess the influence of capsaicin and cold exposure on CRC rat models induced by DMH. The present study reported that capsaicin and cold exposure treatment significantly increased the size and number of colonic tumors, and the CRC metastasis rate in the capsaicin and cold exposure groups was higher than that in DMH model group.Moreover, it was observed that capsaicin and cold exposure increased mRNA and protein expression levels of LAMC2 and integrin-β1 induced by DMH. Duolink PLA results indicated that cold exposure and capsaicin significantly promoted interaction formation between LAMC2 and ITGB1 in CRC rats induced by DMH. Furthermore, western blot and IHC analysis confirmed that cold exposure and capsaicin inhibited DMH-induced decreases in the expression levels of E-cadherin, and increases in the expression levels of p-FAK, Snails, Fibronectin and N-cadherin. In addition, the serum levels of IL-1β and IL-6 in capsaicin and cold exposure group were higher than those of model group. In conclusion, our study suggests that both capsaicin and cold exposure may contribute to EMT-mediated the formation of premetastatic niche, which may lead to CRC metastasis by activating the early interaction between LAMC2 and integrin-β1.

Retraction: Capsaicin and Cold exposure promote EMT-mediated premetastatic niche formation to facilitate colorectal cancer metastasis.

[This retracts the article DOI: 10.7150/jca.83985.].

Heat Shock Proteins Mediate Intercellular Communications within the Tumor Microenvironment through Extracellular Vesicles

From an evolutive perspective, tumor cells endure successive turnover upon stress conditions and pressure to adapt to new environments. These cells use exceptional communication skills to share biological information to “survive upon every metabolic cost”. The tumor microenvironment (TME) is a miscellaneous collection of cells, factors, and extracellular vesicles (EVs). EVs are small lipid bilayer-delimited particles derived from cells with sizes ranging from 100 to 1000 nm. Exosomes (<160 nm) are the minor subtype of EVs, originating from the endosomal pathways. The TME also contains “giant” vesicles, microvesicles (100–1000 nm, MV), originated from membrane blebbing. EVs can act as intercellular communication mediators, contributing to many biological processes, by carrying different biomolecules, such as proteins, lipids, nucleic acids, and metabolites. EV secretion can promote either tumor cell survival or manage their stress to death. Tumor-derived EVs transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat shock proteins (HSP) are prominent stress response regulators, specifically carried by exosomes. HSP-loaded EVs reprogram tumor and TME cells to acquire mechanisms contributing to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from the endoplasmic reticulum stress, hypoxia, apoptosis, and anticancer therapies. Extracellular HSPs activate and deactivate the immune response, induce cell differentiation, change vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we explore EVs’ mechanisms of HSP transmission among TME cells and the relevance of these intercellular communications in resistance to therapy.

Decoding the secret of extracellular vesicles in the immune tumor microenvironment of the glioblastoma: on the border of kingdoms.

Over the last decades, extracellular vesicles (EVs) have become increasingly popular for their roles in various pathologies, including cancer and neurological and immunological disorders. EVs have been considered for a long time as a means for normal cells to get rid of molecules it no longer needs. It is now well established that EVs play their biological roles also following uptake or by the interaction of EV surface proteins with cellular receptors and membranes. In this review, we summarize the current status of EV production and secretion in glioblastoma, the most aggressive type of glioma associated with high mortality. The main purpose is to shed light on the EVs as a universal mediator of interkingdom and intrakingdom communication in the context of tumor microenvironment heterogeneity. We focus on the immunomodulatory EV functions in glioblastoma-immune cross-talk to enhance immune escape and reprogram tumor-infiltrating immune cells. We critically examine the evidence that GBM-, immune cell-, and microbiome-derived EVs impact local tumor microenvironment and host immune responses, and can enter the circulatory system to disseminate and drive premetastatic niche formation in distant organs. Taking into account the current state of the art in intratumoral microbiome studies, we discuss the emerging role of bacterial EV in glioblastoma and its response to current and future therapies including immunotherapies.

Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond.

Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

Abstract B104: U18666A-induced cholesterol accumulation decreases tumor-derived exosomes load and modulates malignant transformation

Abstract Background: Tumor-derived exosomes (TDEs) play an important role in the horizontal transfer of oncogenic information from the tumor to other sites, where they regulate pre-metastatic niche formation, organotropism, migration, invasion and survival. Cellular cholesterol homeostasis emerges as an important factor for exosomal biogenesis and cellular release. In this study, we utilized U18666A to trigger cholesterol accumulation within late endosomes of MDA-MB231 cells and evaluated the ability of exosomes derived from both U18666A-treated and untreated cells to initiate malignant transformation in recipient human epithelial kidney (HEK293) cells. Methods: Exosomes were isolated and characterized from MDA-MB231 (untreated and U18666A-treated) and HEK293 cells. Cholesterol content of the cells and their associated exosomes were measured to confirm its accumulation following U18666A treatment. The effects of exosomes derived from untreated MDA-MB231 (UCE) and U18666A-treated MDA-MB231 (UTCE) cells on HEK293 cells were examined to determine their transforming potential. Results: Exosomes derived from MDA-MB231 cells induced proliferation, migration, malignant transformation and epithelial-mesenchymal transition (EMT) process in non-cancerous recipients’ cells. U18666A treatment led to accumulation of cholesterol within late endosomes and significantly reversed the EMT process in MDA-MB231 cells. It also reduced TAEs load from the cancer cells and rendered them less oncogenic which was evident from their inability to induce malignant transformation in the recipient HEK293 cells. Conclusion: Modulation of cholesterol homeostasis and disruption of cholesterol supply to aggressive cancer cells can be an attractive strategy for limiting TAEs release as well as their subsequent role in cancer progression and metastasis. Citation Format: Syed Sultan Beevi, Vinod Kumar Verma. U18666A-induced cholesterol accumulation decreases tumor-derived exosomes load and modulates malignant transformation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B104.

Blood flow diverts extracellular vesicles from endothelial degradative compartments to promote angiogenesis.

Extracellular vesicles released by tumors (tEVs) disseminate via circulatory networks and promote microenvironmental changes in distant organs favoring metastatic seeding. Despite their abundance in the bloodstream, how hemodynamics affect the function of circulating tEVs remains unsolved. We demonstrated that efficient uptake of tEVs occurs in venous endothelial cells that are subjected to hemodynamics. Low flow regimes observed in veins partially reroute internalized tEVs toward non-acidic and non-degradative Rab14-positive endosomes, at the expense of lysosomes, suggesting that endothelial mechanosensing diverts tEVs from degradation. Subsequently, tEVs promote the expression of pro-angiogenic transcription factors in low flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that low flow regimes potentiate the pro-tumoral function of circulating tEVs by promoting their uptake and rerouting their trafficking. We propose that tEVs contribute to pre-metastatic niche formation by exploiting endothelial mechanosensing in specific vascular regions with permissive hemodynamics.

Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling

BackgroundPulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored. MethodsTDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts. ResultsH-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment. ConclusionThe present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.

Feline mammary carcinoma-derived extracellular vesicle promotes liver metastasis via sphingosine kinase-1-mediated premetastatic niche formation

BackgroundFeline mammary carcinoma (FMC) is one of the most prevalent malignancies of female cats. FMC is highly metastatic and thus leads to poor disease outcomes. Among all metastases, liver metastasis occurs in about 25% of FMC patients. However, the mechanism underlying hepatic metastasis of FMC remains largely uncharacterized.ResultsHerein, we demonstrate that FMC-derived extracellular vesicles (FMC-EVs) promotes the liver metastasis of FMC by activating hepatic stellate cells (HSCs) to prime a hepatic premetastatic niche (PMN). Moreover, we provide evidence that sphingosine kinase 1 (SK1) delivered by FMC-EV was pivotal for the activation of HSC and the formation of hepatic PMN. Depletion of SK1 impaired cargo sorting in FMC-EV and the EV-potentiated HSC activation, and abolished hepatic colonization of FMC cells.ConclusionsTaken together, our findings uncover a previously uncharacterized mechanism underlying liver-metastasis of FMC and provide new insights into prognosis and treatment of this feline malignancy.

Extracellular vesicles – biogenesis and role in cancer treatment

Extracellular vesicles represent a group of cell-derived structures of different sizes encapsulating a variety of molecules. Cargos in exosomes, such as nucleic acids (RNA and DNA), proteins, and lipids serve as external stimuli for recipient cells, thus modifying the intercellular communication pathway in both homeostatic physiological and pathological conditions, including cancer. Due to the heterogeneity of these extracellular vesicles, it has been shown that these vesicles can also carry tumor-associated molecules, favoring the formation of pre-metastatic niches and cancer metastasis. Knowledge of the cellular processes that stand at the basis of their biogenesis and relation with the tumor microenvironment is essential for their potential use for clinical application. This review introduces the expanding and promising field of exosome research focusing on their biogenesis and composition and presenting different methods for their isolation and detection. In addition, this review also discusses their interrelations within the tumor microenvironment and possible use as potential therapeutic targets.

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.

CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages.

The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.

Tumor Angiocrine Signaling: Novel Targeting Opportunity in Cancer.

The vascular endothelium supplies nutrients and oxygen to different body organs and supports the progression of diseases such as cancer through angiogenesis. Pathological angiogenesis remains a challenge as most patients develop resistance to the approved anti-angiogenic therapies. Therefore, a better understanding of endothelium signaling will support the development of more effective treatments. Over the past two decades, the emerging consensus suggests that the role of endothelial cells in tumor development has gone beyond angiogenesis. Instead, endothelial cells are now considered active participants in the tumor microenvironment, secreting angiocrine factors such as cytokines, growth factors, and chemokines, which instruct their proximate microenvironments. The function of angiocrine signaling is being uncovered in different fields, such as tissue homeostasis, early development, organogenesis, organ regeneration post-injury, and tumorigenesis. In this review, we elucidate the intricate role of angiocrine signaling in cancer progression, including distant metastasis, tumor dormancy, pre-metastatic niche formation, immune evasion, and therapy resistance.