Search Results (20)

Breast cancer metastasis remains the primary driver of patient mortality, involving dynamic interactions between tumor cells and distant organ microenvironments. In recent years, tumor cell-derived extracellular vesicles (EVs) have emerged as critical information carriers, playing central roles in breast cancer metastasis by mediating organ-specific pre-metastatic niche formation, immune modulation, and tumor cell adaptive evolution. Studies have demonstrated that EVs drive the metastatic cascade through the delivery of bioactive components, including nucleic acids (e.g., miRNAs, circRNAs), proteins (e.g., integrins, metabolic enzymes), and lipids, which collectively regulate osteoclast activation, immune cell polarization, vascular permeability alterations, and extracellular matrix (ECM) remodeling in target organs such as bone, the lungs, and the liver. Molecular heterogeneity in EVs derived from different breast cancer subtypes strongly correlates with organotropism, providing potential biomarkers for metastasis prediction. Leveraging the organotrophic mechanisms of EVs and their dual regulatory roles in metastasis (pro-metastatic and anti-metastatic), strategies targeting EV biogenesis, cargo loading, or delivery exhibits translational potential in diagnostics and therapeutics. In this review, we summarize recent advances in understanding the role of breast cancer-derived exosomes in mediating metastatic organotropism and discuss the potential clinical applications of targeting exosomes as novel diagnostic and therapeutic strategies for breast cancer. Full article

Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes. Full article

Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic and pro-inflammatory niche is described during organotro-pism and in lymphatic-mediated metastasis. Second, tumor-derived exosomes can transfer molecular signals that induce cell cycle arrest, dormancy, and survival pathways in disseminated cells, promoting a dormant state are reviewed. Third, several studies highlight exosome involvement in maintaining cellular dormancy in the bone marrow endosteum. Finally, the clinical implications of exosomes as biomarkers or diagnostic tools for cancer progression are also outlined. Understanding the complex interplay between tumor-derived exosomes and the pre-metastatic niche is crucial for developing novel therapeutic strategies to target metastasis and prevent cancer recurrence. To that end, several examples of how exosomes or other nanocarriers are used as a drug delivery system to inhibit cancer metastasis are discussed. Strategies are discussed to alter exosome cargo content for better loading capacity or direct cell targeting by integrins. Further, pre-clinical models or Phase I clinical trials implementing exosomes or other nanocarriers to attack metastatic cancer cells are highlighted. Full article

Integrins are cell adhesion receptors, which play a role in breast cancer invasion, angiogenesis, and metastasis. Moreover, it has been shown that exosomal integrins provide organotropic metastasis in a mouse model. In our study, we aimed to investigate the expression of integrins β3, β4, and αVβ5 on exosomes and tumor cells (circulating tumor cells and primary tumor) and their association with the localization of distant metastasis. We confirmed the association of exosomal integrin β4 with lung metastasis in breast cancer patients. However, we were unable to evaluate the role of integrin β3 in brain metastasis due to the rarity of this localization. We established no association of exosomal integrin αVβ5 with liver metastasis in our cohort of breast cancer patients. The further evaluation of β3, β4, and αVβ5 integrin expression on CTCs revealed an association of integrin β4 and αVβ5 with liver, but not the lung metastases. Integrin β4 in the primary tumor was associated with liver metastasis. Furthermore, an in-depth analysis of phenotypic characteristics of β4+ tumor cells revealed a significantly increased proportion of E-cadherin+ and CD44+CD24- cells in patients with liver metastases compared to patients with lung or no distant metastases. Full article

Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved in EV biogenesis and secretion are upregulated in various tumours. Recent studies have revealed that EVs facilitate the interaction between cancer cells and their microenvironment and play a substantial role in the growth of tumours. As EVs are involved in several aspects of cancer progression including angiogenesis, organotropism, pre-metastatic niche formation, fostering of metastasis, and chemoresistance, inhibiting the release of EVs from cancer and the surrounding tumour microenvironment cells has been proposed as an ideal strategy to treat cancer and associated paraneoplastic syndromes. Lately, EVs have shown immense benefits in preclinical settings as a novel drug delivery vehicle. This review provides a brief overview of the role of EVs in various hallmarks of cancer, focusing on (i) strategies to treat cancer by therapeutically targeting the release of tumour-derived EVs and (ii) EVs as valuable drug delivery vehicles. Furthermore, we also outline the drawbacks of the existing anti-cancer treatments and the future prospective of EV-based therapeutics. Full article

Breast cancer has been the most common cancer in women worldwide, and metastasis is the leading cause of death from breast cancer. Even though the study of breast cancer metastasis has been extensively carried out, the molecular mechanism is still not fully understood, and diagnosis and prognosis need to be improved. Breast cancer metastasis is a complicated process involving multiple physiological changes, and lung, brain, bone and liver are the main metastatic targets. Exosomes are membrane-bound extracellular vesicles that contain secreted cellular constitutes. The biogenesis and functions of exosomes in cancer have been intensively studied, and mounting studies have indicated that exosomes play a crucial role in cancer metastasis. In this review, we summarize recent findings on the role of breast cancer-derived exosomes in metastasis organotropism and discuss the potential promising clinical applications of targeting exosomes as novel strategies for breast cancer diagnosis and therapy. Full article

Distant metastases are detrimental for cancer patients, but the increasingly early detection of tumors offers a chance for metastasis prevention. Importantly, cancers do not metastasize randomly: depending on the type of cancer, metastatic progenitor cells have a predilection for well-defined organs. This has been theorized by Stephen Paget, who proposed the “seed-and-soil hypothesis”, according to which metastatic colonization occurs only when the needs of a given metastatic progenitor cell (the seed) match with the resources provided by a given organ (the soil). Here, we propose to explore the seed-and-soil hypothesis in the context of cancer metabolism, thus hypothesizing that metastatic progenitor cells must be capable of detecting the availability of metabolic resources in order to home in a secondary organ. If true, it would imply the existence of metabolic sensors. Using human triple-negative MDA-MB-231 breast cancer cells and two independent brain-seeking variants as models, we report that cyclooxygenase 7b (Cox7b), a structural component of Complex IV of the mitochondrial electron transport chain, belongs to a probably larger family of proteins responsible for breast cancer brain tropism in mice. For metastasis prevention therapy, this proof-of-principle study opens a quest for the identification of therapeutically targetable metabolic sensors that drive cancer organotropism. Full article

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis. Full article

Isolated pancreatic metastases of renal cell carcinoma (isPMRCC) are a rare manifestation of metastatic renal cell carcinoma (mRCC) characterized by two peculiarities: (1). The definite or at least long-term exclusive occurrence of metastases in the pancreas and (2). an unusual low tumour aggressiveness with slow tumour progression and consecutive, good treatment results. According to current knowledge, the exclusive occurrence of pancreatic metastases is due to a highly specific and highly selective seed and soil mechanism, which does not allow metastases settlement outside the pancreas, and whose detailed genetic/epigenetic causes are not yet elucidated. Recent studies have shed light on some of the pathways involved for the protracted course of the disease and highlighted a special genetic profile (lack of loss of 9p, lower weight genome instability index, low frequency of BAP1 alterations, and a high frequency of PBRM1 loss), which deviates from the conventional mRCC profile. Finally, the question of the reasons for the long-term relative genetic stability of the involved cell clones, which is an essential prerequisite for a favourable prognosis, remains unanswered. Full article

While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial–mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection. Full article

Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery. Full article

Brain metastases are the most severe clinical manifestation of aggressive tumors. Melanoma, breast, and lung cancers are the types that prefer the brain as a site of metastasis formation, even if the reasons for this phenomenon still remain to be clarified. One of the main characteristics that makes a cancer cell able to form metastases in the brain is the ability to interact with the endothelial cells of the microvasculature, cross the blood–brain barrier, and metabolically adapt to the nutrients available in the new microenvironment. In this review, we analyzed what makes the brain a suitable site for the development of metastases and how this microenvironment, through the continuous release of neurotransmitters and amino acids in the extracellular milieu, is able to support the metabolic needs of metastasizing cells. We also suggested a possible role for amino acids released by the brain through the endothelial cells of the blood–brain barrier into the bloodstream in triggering the process of extravasation/invasion of the brain parenchyma. Full article

Due to the heterogeneous nature of breast cancer, metastasis organotropism has been poorly understood. This study assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs compared with non-metastatic breast cancer. We found that several secreted mediators encoding genes notably, LCN2 and S100A8 overexpressed at the distant metastatic site spine (LCN2, 5-fold; S100A8, 6-fold) and bone (LCN2, 5-fold; S100A8, 3-fold) vs. primary tumors in the syngeneic implantation/tumor-resection metastasis mouse model. In contrast, the ESM-1 encoding gene is overexpressed in the primary tumors and markedly downregulated at distant metastatic sites. Further digging into TCAGA-BRCA, SCAN-B, and METABRIC cohorts data analysis revealed that LCN2, S100A8, and ESM-1 mediators encoding individual gene expression scores were strongly associated with disease-specific survival (DSS) in the METABRIC cohort (hazard ratio (HR) > 1, p < 0.0004). The gene expression scores predicted worse clinically aggressive tumors, such as high Nottingham histological grade and advanced cancer staging. Higher gene expression score of ESM-1 gene was strongly associated with worse overall survival (OS) in the triple-negative breast cancer (TNBC) and hormonal receptor (HR)-positive/HER2-negative subtype in METABRIC cohort, HER2+ subtype in TCGA-BRCA and SCAN-B breast cancer cohorts. Our data suggested that mediators encoding genes with prognostic and predictive values may be clinically useful for breast cancer spine, bone, and lung metastasis, particularly in more aggressive subtypes such as TNBC and HER2+ breast cancer. Full article

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. Full article

Tumor metastasis involves the dissemination of tumor cells from the primary lesion to other organs and the subsequent formation of secondary tumors, which leads to the majority of cancer-related deaths. Clinical findings show that cancer cell dissemination is not random but exhibits organ preference or organotropism. While intrinsic biochemical factors of cancer cells have been extensively studied in organotropism, much less is known about the role of cell cytoskeleton and mechanics. Herein, we demonstrate that cell cytoskeleton and mechanics are correlated with organotropism. The result of cell stiffness measurements shows that breast cancer cells with bone tropism are much stiffer with enhanced F-actin, while tumor cells with brain tropism are softer with lower F-actin than their parental cells. The difference in cellular stiffness matches the difference in the rigidity of their metastasized organs. Further, disrupting the cytoskeleton of breast cancer cells with bone tropism not only elevates the expressions of brain metastasis-related genes but also increases cell spreading and proliferation on soft substrates mimicking the stiffness of brain tissue. Stabilizing the cytoskeleton of cancer cells with brain tropism upregulates bone metastasis-related genes while reduces the mechanoadaptation ability on soft substrates. Taken together, these findings demonstrate that cell cytoskeleton and biophysical properties of breast cancer subpopulations correlate with their metastatic preference in terms of gene expression pattern and mechanoadaptation ability, implying the potential role of cell cytoskeleton in organotropism. Full article