Search Results (77)

Breast cancer is the most prevalent malignancy among women and a leading cause of morbidity and mortality worldwide. Metastasis—the dissemination of tumor cells to distant organs—is the primary driver of breast cancer-related deaths, often leading to organ dysfunction and treatment resistance. While sentinel lymph nodes are the initial site of metastasis, the molecular mechanisms driving lymphatic spread are still not well understood. Multifarious questions remain on the role, requirement, and significance of the lymphatic system in the context of the distant metastasis of breast cancer. To address these questions, this review explores the recent advancements achieved in studies related to the molecular processes behind lymphatic metastasis in breast cancer, highlighting the tumor microenvironment’s role in supporting circulating tumor cells. We also examine the key molecular pathways involved in metastatic progression by analyzing the cellular, genetic, and physiological factors that drive lymphatic metastasis. The insights gained may contribute to the development of new therapeutic approaches to prevent or mitigate breast cancer metastasis. Full article

Cancer metastasis often accounts for the primary cause of cancer-related mortality, with the lymphatic system playing a pivotal role in the dissemination of malignant cells. While hematogenous vessel spread is commonly associated with distant organ metastasis, the lymphatic system serves as an early conduit for tumor cell invasion and dissemination. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, intravasation into lymphatic vessels, survival, transport, and colonization of regional lymph nodes (LNs). Cancerous cells then establish micro-metastases at the colonized sites and expand in the new microenvironment, ultimately resulting in the generation of secondary tumors. Tumor-secreted factors, such as vascular endothelial growth factors (VEGF-C and VEGF-D), contribute to metastasis through lymphangiogenesis, the formation of new lymphatic vessels. In addition, cancer cells utilize pre-existing chemokine signaling pathways by expressing chemokine receptors, such as CCR7, which bind to chemokine ligands, such as CCL19 and CCL21, to facilitate targeted migration into the lymphatic vessels. LNs are often the initial sites for metastasis and therefore are indicators of distant organ involvement. It is well established that the location and extent of LN involvement provides significant prognostic information, although the optimal treatment approach for LN metastases remains a subject of debate. Understanding the mechanisms of lymphatic metastasis offers potential therapeutic targets to mitigate cancer progression. Full article

EMILIN-1 (Elastin Microfibril Interface Located Protein 1) is an extracellular matrix homotrimeric glycoprotein belonging to the EMILIN/Multimerin family, with both structural and regulatory roles, increasingly recognized for its tumor-suppressive functions. Initially identified for its involvement in elastogenesis and vascular homeostasis, EMILIN-1 has gradually emerged as a key player in cancer biology. It exerts its anti-tumor activity through both direct and indirect mechanisms: by regulating tumor cell proliferation and survival and by modulating lymphangiogenesis and the associated inflammatory microenvironment. At the molecular level, EMILIN-1 inhibits pro-oncogenic signaling pathways, such as ERK/AKT and TGF-β, via its selective interaction with α4/α9 integrins. In the tumor microenvironment, it contributes to tissue homeostasis by restraining aberrant lymphatic vessel formation, a process closely linked to tumor dissemination and immune modulation. Notably, EMILIN-1 expression is frequently reduced or its structure altered by proteolytic degradation in advanced cancers, correlating with disease progression and poor prognosis. This review summarizes the current knowledge on EMILIN-1 in cancer, focusing on its dual function as an active extracellular matrix regulator of intercellular signaling. Particular attention is given to its mechanistic role in the control of cell proliferation, underscoring its potential as a novel biomarker and therapeutic target in oncology. Full article

Systemic cancer progression culminating in metastatic disease is implicitly dependent on tumour cell interactions with the vascular system. Indeed, different facets of the micro- and macro-vasculature can be regarded as rate-limiting ‘vascular checkpoints’ in the process of cancer dissemination. The underlying complex communication networks drive tumour neovascularization, angiogenesis, immunoregulation, activation of the coagulation system, angiocrine interactions, and non-angiogenic vascular responses across multiple cancer types. Yet, each cancer may represent a unique vascular interaction scenario raising a prospect of targeted modulation of blood and lymphatic vessels for therapeutic purposes, beyond the traditional notion of tumour anti-angiogenesis. While the emphasis of studies aiming to understand this circuitry has traditionally been on soluble, or ‘mono-molecular’ mediators, the rise of the particulate secretome encompassing heterogeneous subpopulations of extracellular vesicles (EVs; including exosomes) and particles (EPs) brings another dimension into the tumour–vascular communication web during the process of metastasis. EVs and EPs are nanosized cellular fragments, the unique nature of which lies in their ability to encapsulate, protect and deliver to target cells a range of bioactive molecular entities (proteins, RNA, DNA) assembled in ways that enable them to exert a wide spectrum of biological activities. EVs and EPs penetrate through biological barriers and are capable of intracellular uptake. Their emerging vascular functions in metastatic or infiltrative cancers are exemplified by their roles in pre-metastatic niche formation, thrombosis, vasectasia or angiocrine regulation of cancer stem cells. Here, we survey some of the related evidence supporting the biological, diagnostic and interventional significance of EVs/EPs (EVPs) in disseminated neoplastic disease. Full article

Non-tuberculous mycobacteria (NTM) are saprophytes of both soil and water that may cause infection with a high risk of dissemination, mainly in immunocompromised patients. Most NTM infections occur in the lungs, while uncommon localizations are the skin, soft tissues, musculoskeletal apparatus, and lymphatic system. The possible relationship between NTM infections and dental procedures is still unclear. The authors reported a rare manifestation of NTM infection occurring in a 6-year-old girl who developed sub-mandibular swelling related to a necrotic tooth, thus mimicking an abscess of odontogenic origin. Fine-needle aspiration biopsy of the sub-mandibular swelling and the following microbiologic investigation showed infection sustained by the Mycobacterium fortuitum complex. After the medical and surgical treatment, the patient completely recovered after 8 months. A review of the relevant literature was carried out to deepen the clinical and microbiological aspects of such a rare occurrence. Full article

The lymphatic system, a complex and dynamic network comprising lymphatic vessels, lymph nodes (LNs), and associated lymphoid tissues, plays a pivotal role in regulating interstitial fluid balance and providing immune surveillance across the body. In cancer, however, the lymphatic system often transforms into a pathway for malignant cell dissemination, leading to lymphatic metastasis—a significant step in tumor progression associated with worse patient prognoses. Mechanistically, tumor cells exploit lymphangiogenic pathways to facilitate their entry and spread within the lymphatic network. Key mechanisms in this process include the upregulation of vascular endothelial growth factors C and D (VEGF-C/D), which promote lymphatic endothelial proliferation, vessel dilation, and increased permeability. This review seeks to provide an in-depth examination of the biological mechanisms underpinning lymphatic metastasis, explore its impact on cancer progression, and highlight current and emerging strategies aimed at managing metastatic disease. Full article

Due to the sudden emergence and burnout nature of Marburg virus (MARV) outbreaks, little is known about MARV’s pathogenicity and immunogenicity. These gaps in knowledge are limiting our understanding of the disease and the implementation of cost-effective prevention and control measures including case management through safe and effective therapeutic modalities. Therefore, this review aims to synthesize and summarize evidence about pathogenicity, immunogenicity, and virulence in humans towards MARV. Upon infection, MARV rapidly disseminates throughout various tissues, provoking severe cellular injury, particularly in lymphatic organs, the liver, kidneys, and the gastrointestinal tract. The virus takes advantage of host cells by avoiding immune responses, mainly by disrupting the function of dendritic cells and blocking the signaling pathways for interferon. As a result, patients experience profound immune dysregulation characterized by early lymphocyte depletion and a shift towards pro-inflammatory cytokine release, resulting in a cytokine storm that can lead to hemorrhagic septic shock. Additionally, adaptive immune responses, including antibody production, are impaired, further complicating recovery and increasing susceptibility to severe disease outcomes. Understanding these intricate host–pathogen interactions is critical for developing effective therapeutic strategies and vaccines against MARV. Continuing research is essential to explain the mechanisms of immune evasion and to identify potential intervention points for improving patient outcomes. Full article

Ovarian endometriomas (OEMs), cystic formations within the ovaries, are a significant manifestation of endometriosis and present in 20–40% of affected women. Despite extensive research, the pathogenesis of endometriosis remains unclear, with retrograde menstruation, coelomic metaplasia, and lymphatic dissemination being proposed mechanisms. OEMs negatively impact ovarian function by reducing the ovarian reserve, disrupting folliculogenesis, and altering the ovarian microenvironment through oxidative stress, inflammation, and fibrosis. Elevated reactive oxygen species (ROS) accelerate follicular atresia, and extracellular matrix remodeling contributes to ovarian damage, while immune dysregulation and cytokine imbalances further exacerbate the condition. The presence of OEMs does not significantly affect live birth rates in in vitro fertilization (IVF) treatments, despite potential reductions in the quality and quantity of oocytes. However, their surgical excision compromises the ovarian reserve. This review highlights the complex mechanisms by which OEMs impair ovarian function and emphasizes the need for further research to develop strategies that mitigate these effects, ultimately improving reproductive outcomes for women with endometriomas. Full article

Background/Objectives: Cervical cancer primarily disseminates through the lymphatic system, with the metastatic involvement of pelvic and para-aortic lymph nodes significantly impacting prognosis and treatment decisions. Sentinel lymph node (SLN) mapping is critical in guiding surgical management. However, resource-limited settings often lack advanced detection tools like indocyanine green (ICG). This study evaluated the feasibility and effectiveness of SLN biopsy using alternative techniques in a high-risk population with a high prevalence of large tumours. Methods: This prospective, observational study included 42 patients with FIGO 2018 stage IA1–IIA1 cervical cancer treated between November 2019 and April 2024. SLN mapping was performed using methylene blue alone or combined with a technetium-99m radiotracer. Detection rates, sensitivity, and false-negative rates were analysed. Additional endpoints included tracer technique comparisons, SLN localization patterns, and factors influencing detection success. Results: SLNs were identified in 78.6% of cases, with bilateral detection in 57.1%. The combined technique yielded higher detection rates (93.3% overall, 80% bilateral) compared to methylene blue alone (70.4% overall, 40.7% bilateral, p < 0.05). The sensitivity and negative predictive values were 70% and 93.87%, respectively. Larger tumours (>4 cm), deep stromal invasion, and prior conization negatively impacted detection rates. False-negative SLNs were associated with larger tumours and positive lymphovascular space invasion. Conclusions: SLN biopsy is feasible in resource-limited settings, with improved detection rates using combined tracer techniques. However, sensitivity remains suboptimal due to a steep learning curve and challenges in high-risk patients. Until a high detection accuracy is achieved, SLN mapping should complement, rather than replace, pelvic lymphadenectomy in high-risk cases. Full article

Many viruses induce viremia (virus in the blood) and disseminate throughout the body via the bloodstream from the initial infection site. However, viruses must often pass through the lymphatic system to reach the blood. The lymphatic system comprises a network of vessels distinct from blood vessels, along with interconnected lymph nodes (LNs). The complex network has become increasingly appreciated as a crucial host factor that contributes to both the spread and control of viral infections. Viruses can enter the lymphatics as free virions or along with migratory cells. Once virions arrive in the LN, sinus-resident macrophages remove infectious virus from the lymph. Depending on the virus, macrophages can eliminate infection or propagate the virus. A virus released from an LN is eventually deposited into the blood. This unique pathway highlights LNs as targets for viral infection control and for modulation of antiviral response development. Here, we review the lymphatic system and viruses that disseminate through this network. We discuss infection of the LN, the generation of adaptive antiviral immunity, and current knowledge of protection within the infected node. We conclude by sharing insights from ongoing efforts to optimize lymphatic targeting by vaccines and pharmaceuticals. Understanding the lymphatic system’s role during viral infection enhances our knowledge of antiviral immunity and virus–host interactions and reveals potential targets for next-generation therapies. Full article

Pigment epithelium-derived factor (PEDF) is a multifunctional soluble glycoprotein, primarily known for its potent anti-angiogenic properties. In recent years, its ability to counteract cell proliferation and motility has generated interest in PEDF as a potential tumor suppressor. In the intrahepatic Cholangiocarcinoma (iCCA), PEDF, Thrombospondin 1 (THBS1), and Thrombospondin 2 (THBS2) are expressed and released into the tumor microenvironment (TME), where they promote lymphangiogenesis at the expense of the neoangiogenic program, aiding the dissemination of cancer cells via lymphatic vessels. Recently, we demonstrated that THBS1 and THBS2 directly affect iCCA cells, exacerbating their malignant behavior, while the direct role of PEDF remains to be elucidated. In this study, through a cell-based assay and molecular analysis, we investigate the direct function of PEDF on two well-established iCCA cell lines. Our results show that PEDF affects cancer cell motility in a paracrine manner, reducing their migratory and invasive capabilities. Notably, our data suggest that the PEDF-induced inhibition of motility in iCCA cells occurs through the MAPK/ERK signaling pathway, as indicated by the reduced phosphorylation of ERK1/2. Overall, this study provides the first evidence of PEDF acting as a tumor suppressor in iCCA. Full article

Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma–vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma–vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine–chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination. Full article

Sporotrichosis is a type of zoonotic subcutaneous mycosis caused by different species of dimorphic fungus of the genus Sporothrix, and it is the most common form of subcutaneous mycosis in Latin America. Sporotrichosis is generally restricted to cutaneous and lymphatic tissue (i.e., localized forms), and involvement in the viscera (i.e., disseminated or disseminated cutaneous form) is uncommon, especially in the central nervous system. However, immunosuppression in individuals with diabetes mellitus can lead to the disseminated form of the disease due to a failure to eliminate the pathogen and poor infection treatment outcomes. Possible correlations between patients with diabetes and their greater susceptibility to disseminated cases of sporotrichosis include a decreased cytokine response after stimulation, increased oxidative stress, decreased chemotaxis, phagocytic activity, adhesion and rolling of neutrophils and monocytes/macrophages, and increased macrophage/monocyte and polymorphonuclear cell apoptosis. Therefore, this review highlights novel insights into diabetes and sporotrichosis by investigating how chronic inflammation affects and aggravates the infection, the possible causes of the greater susceptibility of Sporothrix sp. to hematogenous dissemination in immunocompromised patients, and the main alterations that this dissemination can cause. Full article

Targeted axillary dissection (TAD), employing marked lymph node biopsy (MLNB) alongside sentinel lymph node biopsy (SLNB), is increasingly recognised for its efficacy in reducing false negative rates (FNRs) in node-positive early breast cancer patients receiving neoadjuvant systemic therapy (NST). One such method, ¹²⁵I radioactive seed localisation (RSL), involves implanting a seed into a biopsy-proven lymph node either pre- or post-NST. This systematic review and pooled analysis aimed to assess the performance of RSL in TAD among node-positive patients undergoing NST. Six studies, encompassing 574 TAD procedures, met the inclusion criteria. Results showed a 100% successful deployment rate, with a 97.6% successful localisation rate and a 99.8% retrieval rate. Additionally, there was a 60.0% concordance rate between SLNB and MLNB. The FNR of SLNB alone was significantly higher than it was for MLNB (18.8% versus 5.3%, respectively; p = 0.001). Pathological complete response (pCR) was observed in 44% of cases (248/564). On average, the interval from ¹²⁵I seed deployment to surgery was 75.8 days (range: 0–272). These findings underscore the efficacy of RSL in TAD for node-positive patients undergoing NST, enabling precise axillary pCR identification and facilitating the safe omission of axillary lymph node dissection. Full article

Background: Clear cell sarcoma (CCS) is an extremely rare form of sarcoma representing less than 1% of all soft-tissue sarcomas. It has morphological, structural, and immunohistochemical similarities to malignant melanoma, affecting young adults and equally affecting both sexes, and is usually located in the tendinous sheaths and aponeuroses of the limbs. Gastrointestinal localization is exceptional, with less than 100 cases reported thus far. The gene fusion of activating transcription factor 1 (ATF1) and the Ewing sarcoma breakpoint region 1 (EWSR1) are pathognomonic for clear cell sarcoma, representing the key to the diagnosis. CCS is an extremely aggressive tumor, with >30% having distant or lymphatic metastasis at the time of diagnostic, and it has a high recurrence rate of over 80% in the first year after diagnosis and a high tendency for metastatic dissemination. Given the rarity of this tumor, there is no standardized treatment. Early diagnosis and radical surgery are essential in the treatment of CCS both for the primary tumor and for recurrence or metastasis. Chemo-radiotherapy has very little effect and is rarely indicated, and the role of targeted therapies is still under investigation. Case presentation: We present an extremely rare case of intestinal CSS in a 44-year-old Caucasian female. The patient, asymptomatic, first presented for a routine checkup and was diagnosed with mild iron-deficiency anemia. Given her family history of multiple digestive cancers, additional investigations were requested (gastroscopy, colonoscopy, tumoral markers and imaging) and the results were all within normal limits. In the subsequent period, the patient experienced mild diffuse recurrent abdominal pain, which occurred every 2–3 months. Two years later, the patient presented with symptoms of intestinal obstruction and underwent an emergency laparotomy followed by segmental enterectomy and regional lymphadenectomy for stenotic tumor of the jejunum. Histology, immunohistochemistry, and genetic testing established the diagnosis of CCS. No adjuvant therapy was indicated. Initially, no signs of recurrence or metastasis were detected, but after 30 and 46 months, respectively, from the primary treatment, the patient developed liver metastasis and pericolic peritoneal implants treated by atypical hepatic resections and right hemicolectomy. The patient remains under observation. Full article