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Human papillomaviruses (HPVs) and, specifically, high-risk HPVs (HR-HPVs) are identified as necessary factors in the development of cancer of the lower genital tract, with CaCU standing out as the most prevalent tumor. This review summarizes ten mechanisms activated by HR-HPVs during cervical carcinogenesis, which are broadly associated with at least seven of the fourteen distinctive physiological capacities of cancer in the newly established model by Hanahan in 2022. These mechanisms involve infection by human papillomavirus, cellular tropism, genetic predisposition to uterine cervical cancer (CaCU), viral load, viral physical state, regulation of epigenetic mechanisms, loss of function of the E2 protein, deregulated expression of E6/E7 oncogenes, regulation of host cell protein function, and acquisition of the mesenchymal phenotype.

Merkel cell carcinoma (MCC) is a very aggressive skin tumor that often causes local recurrence and metastasis. Due to the low morbidity and the older age of the patients, comparative studies on different treatment options at different stages of the disease have not been possible, and there is no consensus on the therapeutic actions to be taken. The pathogenesis of MCC is unknown, but ultraviolet light, immunosuppression, and the presence of polyomavirus in the tumor genome appear to play an important role in the development of this tumor. Pathological diagnosis is difficult because it can be easily confused with cutaneous metastases from other tumors: Ewing sarcoma, small cell lung tumors or neuroblastoma. A 60-year-old male patient is reported to have a 12-month-old tumor and progressive growth in the right elbow. An erythematous nodule is evident, approximately 3x3 cm and firm in consistency., El carcinoma de células de Merkel (CCM) es un tumor cutáneo muy agresivo que a menudo provoca recurrencia local y metástasis. Debido a la baja morbilidad y la mayor edad de los pacientes, no han sido posibles estudios comparativos sobre diferentes opciones de tratamiento en diferentes etapas de la enfermedad, y no existe consenso sobre las acciones terapéuticas a tomar. Se desconoce la patogénesis del CCM, pero la luz ultravioleta, la inmunosupresión y la presencia de poliomavirus en el genoma del tumor parecen jugar un papel importante en el desarrollo de este tumor. El diagnóstico patológico es difícil porque puede confundirse fácilmente con metástasis cutáneas de otros tumores: sarcoma de Ewing, tumores pulmonares de células pequeñas o neuroblastoma. Se reporta paciente masculino de 60 años presenta una tumoración de 12 meses de evolución y crecimiento progresivo en codo derecho. Se evidencia nódulo eritematoso, de aproximadamente 3x3 cm y de consistencia firme.

Background: While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated. Methods: We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta-analysis. To delve deeper, we employed Weighted Gene Co-expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis. Results: Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta-analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis-related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis-related network, and IRF1 was identified as a predictive marker for both recurrence-free and distant metastasis-free survival across multiple datasets. Conclusion: Geographical and ethnic factors might influence peculiarities in MMR protein loss. Ou, This work was supported by the Research Foundation of Outstanding Young Scholars of Sichuan University (Grant No. 2016SCU04B04, C Wang), Natural Science Foundation of Sichuan Province, China (Grant No. 2022NSFSC0764, CW Fan), the Fundamental Research Funds for the Central Universities (Grant No.2022SCU12025 and 2022SCU12020, CW Fan and FW Long), and Swedish Cancer Foundation and Swedish Research Council (XF Sun).

Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

Metastasis is the leading cause of cancer mortality. Metastatic cancer is notoriously difficult to treat, and it accounts for the majority of cancer-related deaths. The ether lipid edelfosine is the prototype of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs, and its antitumor activity involves lipid raft reorganization. In this study, we examined the effect of edelfosine on metastatic colonization and angiogenesis. Using non-invasive bioluminescence imaging and histological examination, we found that oral administration of edelfosine in nude mice significantly inhibited the lung and brain colonization of luciferase-expressing 435-Lung-eGFP-CMV/Luc metastatic cells, resulting in prolonged survival. In metastatic 435-Lung and MDA-MB-231 breast cancer cells, we found that edelfosine also inhibited cell adhesion to collagen-I and laminin-I substrates, cell migration in chemotaxis and wound-healing assays, as well as cancer cell invasion. In 435-Lung and other MDA-MB-435-derived sublines with different organotropism, edelfosine induced G2/M cell cycle accumulation and apoptosis in a concentration- and time-dependent manner. Edelfosine also inhibited in vitro angiogenesis in human and mouse endothelial cell tube formation assays. The antimetastatic properties were specific to cancer cells, as edelfosine had no effects on viability in non-cancerous cells. Edelfosine accumulated in membrane rafts and endoplasmic reticulum of cancer cells, and membrane raft-located CD44 was downregulated upon drug treatment. Taken together, this study highlights the potential of edelfosine as an attractive drug to prevent metastatic growth and organ colonization in cancer therapy. The raft-targeted drug edelfosine displays a potent activity against metastatic organ colonization and angiogenesis, two major hallmarks of tumor malignancy.

Merkel cell carcinoma (MCC) is a very aggressive skin tumor that often causes local recurrence and metastasis. Due to the low morbidity and the older age of the patients, comparative studies on different treatment options at different stages of the disease have not been possible, and there is no consensus on the therapeutic actions to be taken. The pathogenesis of MCC is unknown, but ultraviolet light, immunosuppression, and the presence of polyomavirus in the tumor genome appear to play an important role in the development of this tumor. Pathological diagnosis is difficult because it can be easily confused with cutaneous metastases from other tumors: Ewing sarcoma, small cell lung tumors or neuroblastoma. A 60-year-old male patient is reported to have a 12-month-old tumor and progressive growth in the right elbow. An erythematous nodule is evident, approximately 3x3 cm and firm in consistency., El carcinoma de células de Merkel (CCM) es un tumor cutáneo muy agresivo que a menudo provoca recurrencia local y metástasis. Debido a la baja morbilidad y la mayor edad de los pacientes, no han sido posibles estudios comparativos sobre diferentes opciones de tratamiento en diferentes etapas de la enfermedad, y no existe consenso sobre las acciones terapéuticas a tomar. Se desconoce la patogénesis del CCM, pero la luz ultravioleta, la inmunosupresión y la presencia de poliomavirus en el genoma del tumor parecen jugar un papel importante en el desarrollo de este tumor. El diagnóstico patológico es difícil porque puede confundirse fácilmente con metástasis cutáneas de otros tumores: sarcoma de Ewing, tumores pulmonares de células pequeñas o neuroblastoma. Se reporta paciente masculino de 60 años presenta una tumoración de 12 meses de evolución y crecimiento progresivo en codo derecho. Se evidencia nódulo eritematoso, de aproximadamente 3x3 cm y de consistencia firme.

Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors that support tumor growth. Heparanase expression is upregulated in human carcinomas, sarcomas, and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter postoperative survival of cancer patients, and encouraging the development of heparanase inhibitors as anti-cancer drugs. Among these are heparin/HS mimetics, the only heparanase-inhibiting compounds that are being evaluated in clinical trials. We have synthesized dicarboxylated oxy-heparins (DCoxHs) containing three carboxylate groups per split residue (DC-Hep). The resulting lead compound (termed XII) was upscaled, characterized, and examined for its effectiveness in tumor models. Potent anti-tumorigenic effects were obtained in models of pancreatic carcinoma, breast cancer, mesothelioma, and myeloma, yielding tumor growth inhibition (TGI) values ranging from 21 to 70% and extending the survival time of the mice. Of particular significance was the inhibition of spontaneous metastasis in an orthotopic model of breast carcinoma following resection of the primary tumor. It appears that apart from inhibition of heparanase enzymatic activity, compound XII reduces the levels of heparanase protein and inhibits its cellular uptake and activation. Heparanase-dependent and -independent effects of XII are being investigated. Collectively, our pre-clinical studies with compound XII strongly justify its examination in cancer patients.

Background Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted 0protein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. Results We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV- MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. Conclusions As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites

Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

Potential under- and overtreatment of patients with colorectal cancer liver metastases (CRLM) is considered a clinical problem. Proper patient selection for local and/or systemic treatment strategies may improve outcome in these patients. So, this thesis aimed to tailor personalized treatment plans by making multidisciplinary liver expertise more accessible and to provide new insights in treatment of early recurrent CRLM. Additionally, the performance of radiomics in predicting response to treatment was evaluated. The added value of a dedicated multidisciplinary panel of liver specialists to assess feasibility of local treatment strategies in patients suffering from CRLM is studied in Chapter 2. Diagnostic imaging were reviewed by an expert panel consisting of four hepatobiliary surgeons and two interventional radiologists. In 20.0% of patients initially assigned to systemic treatment of CRLM, upfront local treatment was deemed feasible after re-evaluation by this expert panel. Assessment by such panels may reduce undertreatment of patients with CRLM. The implementation of an online expert panel in clinical practice is reported in Chapter 3. This quality improvement initiative was introduced to provide non-liver centers with online multidisciplinary liver expertise and select patients for referral. Chapter 4 highlights the rules and regulations, which apply for e-consultation services, under current legislation in the Netherlands. There are no legal obstacles or practical objections to the introduction of expert panels in clinical practice, provided that these requirements are met. Chapter 5 describes the perspectives of patients on the use of online expert panels in transmural care. Based on two focus groups, three major themes were identified: ‘data management’, ‘expertise’, and ‘information and coordination’. The potential hazard of privacy violation associated with digital data exchange was accepted, provided that the use of digital data supported a higher purpo

Breast cancer is the most commonly diagnosed and leading cause of cancer death among women worldwide. Mitogen-activated protein kinase-interacting kinases (MNKs) promote the expression of several oncogenic proteins and are overexpressed in several types of cancer. In human cells, there are four isoforms of MNKs. The truncated isoform MNK1b, first described in our laboratory, has a higher basal activity and is constitutively active. Aptamers are emerging in recent years as potential therapeutic agents that show significant advantages over drugs of other nature. We have previously obtained and characterized a highly specific aptamer against MNK1b, named apMNK2F, with a dissociation constant in the nanomolar range, which produces significant inhibition of proliferation, migration, and colony formation in breast cancer cells. Furthermore, its sequence analysis predicted two G-quadruplex structures. In this work, we show the optimization process of the aptamer to reduce its size, improving its stability. The obtained aptamer, named apMNKQ2, is able to inhibit proliferation, colony formation, migration, and invasion in breast cancer cells. In murine models of breast cancer, apMNKQ2 has demonstrated its efficacy in reducing tumor volume and the number of metastases. In conclusion, apMNKQ2 could be used as an anti-tumor drug in the future., Ministerio de Economía y Competitividad, Ministerio de Ciencia, Innovación y Universidades, Ministerio de Ciencia e Innovación (MCIN) / AEI /10.13039/501100011033, Comunidad de Madrid, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, Fac. de Ciencias Químicas, TRUE, pub

Important developments in chemotherapy for metastatic colorectal cancer over the last years are reviewed, with an emphasis on the most recently published data from clinical trials. The systematic review of current literature was conducted involving Pubmed Central® research and full articles were obtained and analyzed when propriate. Fluorouracil still constitutes the backbone of metastatic colorectal cancer treatment; fluorouracil combination plus either irinotecan (FOLFIRI), oxaliplatin (FOLFOX) or capecitabine (CAPOX or XELOX) are chemotherapy protocols established as treatments producing similar outcomes. Actual treatment involves these chemotherapy protocols in combination with new molecular targeted drugs: bevacizumab and aflibercept (anti-vascular endothelial growth factor monoclonal antibody) and cetuximab and panitumumab (anti-epidermal growth factor receptor monoclonal Antibody for patients with wild type KRAS) which confer significant survival benefits in select patients as first- or second-line therapies. The factors affecting the decisions for one treatment over other are related to the patient and toxicity drug. Finally, metastatic colorectal cancer patients progressing after all standard therapies (maintaining a good ECOG performance status) could be candidates for further therapies such as regorafenib and TAS-102. Regarding the future, promising therapies are under development for the metastatic colorectal cancer treatment and several agents are currently being evaluated in different clinical trials, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, Instituto Universitario de Farmacia Industrial, TRUE, pub

Metastasis represents one of the most dangerous issue of cancer progression, characterized by intricate interactions between invading tumor cells, various proteins, and other cells on the way towards target sites. Tumor cells, while undergoing metastasis, engage in dynamic dialogues with stromal cells and undertake epithelial-mesenchymal transition (EMT) phenoconversion. To ensure survival, tumor cells employ several strategies such as restructuring their metabolic needs to adapt to the alterations of the microenvironmental resources via different mechanisms including macroautophagy (autophagy) and to circumvent anoikis—a form of cell death induced upon detachment from the extracellular matrix (ECM). This review focuses on the puzzling connections of autophagy and energetic metabolism within the context of cancer metastasis., Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación MCIN/AEI/10.13039/501100011033, European Union "NextGenerationEU/PRTR", NextGenerationEU (PNRR “HEAL ITALIA - Health Extended Alliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine”, project: PE00000019, CUP: B33C22001030006), Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, inpress

Background: Endometrial cancer recurrence occurs in about 18 % of patients. This study aims to analyze the pattern recurrence of endometrial cancer and the relationship between the initial site of primary disease and the relapse site in patients undergoing surgical treatment. Methods: We retrospectively reviewed all surgically treated patients with endometrial cancer selecting those with recurrence. We defined primary site disease as uterus, lymph nodes, or peritoneum according to pathology analysis of the surgical specimen. The site of recurrence was defined as vaginal cuff, lymph nodes, peritoneum, and parenchymatous organs. Our primary endpoint was to correlate the site of initial disease with the site of recurrence. Results: The study enrolled 1416 patients. The overall recurrence rate was 17,5 % with 248 relapses included in the study. An increase of 9.9, 5.7, and 5.7 times in the odds of relapse on the lymph node, peritoneum, and abdominal parenchymatous sites respectively was observed in case of nodal initial disease (p < 0.001). A not significant difference in odds was observed in terms of vaginal cuff relapse (OR 0.9) between lymph node ad uterine primary disease (p = 0.78). An increasing OR of 8.7 times for nodal recurrences, 46.6 times for peritoneum, and 23.3 times for parenchymatous abdominal recurrences were found in the case of primary peritoneal disease (p < 0.001). Conclusion: Endometrial cancer tends to recur at the initial site of the disease. Intraoperative inspection of the adjacent sites of primary disease and targeted instrumental examination of the initial sites of disease during follow-up are strongly recommended.

Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53−/− cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy.

Background and objectivesGiven advances in therapies, endoprosthetic reconstruction (EPR) in metastatic bone disease (MBD) may be increasingly indicated. The objectives were to review the indications, and implant and patient survivorship in patients undergoing EPR for MBD.MethodsA review of patients undergoing EPR for extremity MBD between 1992 and 2022 at two centers was performed. Surgical data, implant survival, patient survival, and implant failure modes were examined.ResultsOne hundred fifteen patients were included with a median follow-up of 14.9 months (95% confidence interval [CI]: 9.2-19.3) and survival of 19.4 months (95% CI: 13.6-26.1). The most common diagnosis was renal cell carcinoma (34/115, 29.6%) and the most common location was proximal femur (43/115, 37.4%). Indications included: actualized fracture (58/115, 50.4%), impending fracture (30/115, 26.1%), and failed fixation (27/115, 23.5%). Implant failure was uncommon (10/115, 8.7%). Patients undergoing EPR for failed fixation were more likely to have renal or lung cancer (p = 0.006).ConclusionsEPRs were performed most frequently for renal cell carcinoma and in patients with a relatively favorable survival. EPR was indicated for failed previous fixation in 23.5% of cases, emphasizing the importance of predictive survival modeling. EPR can be a reliable and durable surgical option for patients with MBD.

Cell migration through the 3D extracellular matrix (ECM) is a fundamental behavior that has profound importance for both normal and pathological physiology. Despite the ubiquity and necessity of cell migration, it is not well understood how complex cell-environment interactions integrate to drive emergent migration behaviors. This dissertation helps resolve important questions related to how cells move within 3D environments, leading to novel insights relevant to both basic and applied biological questions. Chapter 1 describes a novel biophysical imaging platform capable of measuring multiple cell-ECM interactions simultaneously within 3D environments. This approach reveals how cytoskeletal, adhesion, contractility, and matrix remodeling machinery are coordinated by cells to achieve different modes of movement and how cell-matrix interactions can be used to predict cell migration. This in turn provides critical insights into the sources of migration heterogeneity and reveals a breakdown in the universal coupling of speed and persistence law regulated by adhesion through integrin beta 1. In Chapter 2, migration heterogeneity is leveraged to identify the differential regulation of gene expression that results from distinct modes of cell-matrix interactions, revealing a central role for iron in regulating 3D migration through both biophysical and metabolic pathways. Early upregulation of the enzyme heme oxygenase-1 (Hmox1) promotes invasive migration through endogenous free-iron generation, and the iron-sensitive enzyme aconitase-1 (Aco1) is identified as a sustained marker of invasive migration. The findings and discussion presented in this dissertation represent key advances in methodology, analysis, and biological insight related to 3D cell migration.

Background: EMT has been proposed to be a crucial early event in cancer metastasis. EMT is rigidly regulated by the action of several EMT-core transcription factors, particularly ZEB1. We previously revealed an unusual role of ZEB1 in the S100A8/A9-mediated metastasis in breast cancer cells that expressed ZEB1 at a significant level and showed that the ZEB1 was activated on the MCAM-downstream pathway upon S100A8/A9 binding. ZEB1 is well known to require Zn2+ for its activation based on the presence of several Zn-finger motifs in the transcription factor. However, how Zn2+-binding works on the pleiotropic role of ZEB1 through cancer progression has not been fully elucidated. Methods: We established the engineered cells, MDA-MB-231 MutZEB1 (MDA-MutZEB1), that stably express MutZEB1 (Delta Zn). The cells were then evaluated in vitro for their invasion activities. Finally, an RNA-Seq analysis was performed to compare the gene alteration profiles of the established cells comprehensively. Results: MDA-MutZEB1 showed a significant loss of the EMT, ultimately stalling the invasion. Inclusive analysis of the transcription changes after the expression of MutZEB1 (Delta Zn) in MDA-MB-231 cells revealed the significant downregulation of LOX family genes, which are known to play a critical role in cancer metastasis. We found that LOXL1 and LOXL4 remarkably enhanced cancer invasiveness among the LOX family genes with altered expression. Conclusions: These findings indicate that ZEB1 potentiates Zn2+-mediated transcription of plural EMT-relevant factors, including LOXL1 and LOXL4, whose upregulation plays a critical role in the invasive dissemination of breast cancer cells.

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

Purpose To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. Methods We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. Results In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. Conclusion The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

Background: The incidence of breast cancer metastasis has decreased over the years. However, 20–30% of patients with early breast cancer still die from metastases. The purpose of this study is to evaluate the performance of a Deep Learning Convolutional Neural Networks (CNN) model to predict the risk of distant metastasis using 3T-MRI DCE sequences (Dynamic Contrast-Enhanced). Methods: A total of 157 breast cancer patients who underwent staging 3T-MRI examinations from January 2011 to July 2022 were retrospectively examined. Patient data, tumor histological and MRI characteristics, and clinical and imaging follow-up examinations of up to 7 years were collected. Of the 157 MRI examinations, 39/157 patients (40 lesions) had distant metastases, while 118/157 patients (120 lesions) were negative for distant metastases (control group). We analyzed the role of the Deep Learning technique using a single variable size bounding box (SVB) option and employed a Voxel Based (VB) NET CNN model. The CNN performance was evaluated in terms of accuracy, sensitivity, specificity, and area under the ROC curve (AUC). Results: The VB-NET model obtained a sensitivity, specificity, accuracy, and AUC of 52.50%, 80.51%, 73.42%, and 68.56%, respectively. A significant correlation was found between the risk of distant metastasis and tumor size, and the expression of PgR and HER2. Conclusions: We demonstrated a currently insufficient ability of the Deep Learning approach in predicting a distant metastasis status in patients with BC using CNNs.

Simple Summary Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate the possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo lung metastatic model. We found that highly metastatic TNBC cells have limited iron metabolism and can be more effectively targeted by iron chelators. Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM

Background: The incidence of breast cancer metastasis has decreased over the years. However, 20–30% of patients with early breast cancer still die from metastases. The purpose of this study is to evaluate the performance of a Deep Learning Convolutional Neural Networks (CNN) model to predict the risk of distant metastasis using 3T-MRI DCE sequences (Dynamic Contrast-Enhanced). Methods: A total of 157 breast cancer patients who underwent staging 3T-MRI examinations from January 2011 to July 2022 were retrospectively examined. Patient data, tumor histological and MRI characteristics, and clinical and imaging follow-up examinations of up to 7 years were collected. Of the 157 MRI examinations, 39/157 patients (40 lesions) had distant metastases, while 118/157 patients (120 lesions) were negative for distant metastases (control group). We analyzed the role of the Deep Learning technique using a single variable size bounding box (SVB) option and employed a Voxel Based (VB) NET CNN model. The CNN performance was evaluated in terms of accuracy, sensitivity, specificity, and area under the ROC curve (AUC). Results: The VB-NET model obtained a sensitivity, specificity, accuracy, and AUC of 52.50%, 80.51%, 73.42%, and 68.56%, respectively. A significant correlation was found between the risk of distant metastasis and tumor size, and the expression of PgR and HER2. Conclusions: We demonstrated a currently insufficient ability of the Deep Learning approach in predicting a distant metastasis status in patients with BC using CNNs.

Background: The incidence of breast cancer metastasis has decreased over the years. However, 20–30% of patients with early breast cancer still die from metastases. The purpose of this study is to evaluate the performance of a Deep Learning Convolutional Neural Networks (CNN) model to predict the risk of distant metastasis using 3T-MRI DCE sequences (Dynamic Contrast-Enhanced). Methods: A total of 157 breast cancer patients who underwent staging 3T-MRI examinations from January 2011 to July 2022 were retrospectively examined. Patient data, tumor histological and MRI characteristics, and clinical and imaging follow-up examinations of up to 7 years were collected. Of the 157 MRI examinations, 39/157 patients (40 lesions) had distant metastases, while 118/157 patients (120 lesions) were negative for distant metastases (control group). We analyzed the role of the Deep Learning technique using a single variable size bounding box (SVB) option and employed a Voxel Based (VB) NET CNN model. The CNN performance was evaluated in terms of accuracy, sensitivity, specificity, and area under the ROC curve (AUC). Results: The VB-NET model obtained a sensitivity, specificity, accuracy, and AUC of 52.50%, 80.51%, 73.42%, and 68.56%, respectively. A significant correlation was found between the risk of distant metastasis and tumor size, and the expression of PgR and HER2. Conclusions: We demonstrated a currently insufficient ability of the Deep Learning approach in predicting a distant metastasis status in patients with BC using CNNs.

Objective: HER2 status in breast cancer is an essential parameter in individual therapeutic decision-making and is routinely assessed in primary tumors in accordance with international recommendations. Reports of HER2 heterogeneity raise the question of basing treatment decisions on HER2 status in metastases, if present. We investigated the degree and clinical implications of HER2 heterogeneity in lymph node-positive breast cancer. Because of recent recognition of therapeutic opportunities in this group of tumors, we especially focused on cases involving low-level HER2 expression. Methods: The HER2 status of primary tumors and of corresponding lymph node metastases was determined in archived material at the protein and gene levels using the gene- protein assay and interpreted in accordance with 2018 ASCO/CAP criteria. HER2-low status was defined as protein expression levels 1+ or 2+ with negative amplification status. Results: We analyzed a series of 43 cases of primary infiltrating breast cancer, each with at least two axillary nodes harboring macrometastases (>2 mm), in total 206 such nodes. In 7% of cases, we detected intertumoral HER2 heterogeneity. Three of nine HER2-positive primary tumors were associated with HER2-negative metastases. No cases with HER2-negative primary tumors had HER2-positive metastases, but 55% (6/11) of HER2 0 primary tumors had HER2 1+ and/or 2+ metastases, and 19% (3/16) HER2 1+ cases had exclusively HER2 0 metastases. All metastases in HER2 2+ cases showed HER2-low protein expression levels. Internodal HER2 heterogeneity at low protein expression levels (presence of HER2 0, HER2 1+, and/or HER2 2+ metastatic deposits within the same axilla) was seen in 40% (17/43) of cases. We found no statistically significant association between HER2 heterogeneity and other tumor-related parameters. Survival data indicated worse outcomes in the HER2-low group compared with the rest of the cohort. Conclusion: Our results indicate a substantial inst

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

Objective: HER2 status in breast cancer is an essential parameter in individual therapeutic decision-making and is routinely assessed in primary tumors in accordance with international recommendations. Reports of HER2 heterogeneity raise the question of basing treatment decisions on HER2 status in metastases, if present. We investigated the degree and clinical implications of HER2 heterogeneity in lymph node-positive breast cancer. Because of recent recognition of therapeutic opportunities in this group of tumors, we especially focused on cases involving low-level HER2 expression. Methods: The HER2 status of primary tumors and of corresponding lymph node metastases was determined in archived material at the protein and gene levels using the gene- protein assay and interpreted in accordance with 2018 ASCO/CAP criteria. HER2-low status was defined as protein expression levels 1+ or 2+ with negative amplification status. Results: We analyzed a series of 43 cases of primary infiltrating breast cancer, each with at least two axillary nodes harboring macrometastases (>2 mm), in total 206 such nodes. In 7% of cases, we detected intertumoral HER2 heterogeneity. Three of nine HER2-positive primary tumors were associated with HER2-negative metastases. No cases with HER2-negative primary tumors had HER2-positive metastases, but 55% (6/11) of HER2 0 primary tumors had HER2 1+ and/or 2+ metastases, and 19% (3/16) HER2 1+ cases had exclusively HER2 0 metastases. All metastases in HER2 2+ cases showed HER2-low protein expression levels. Internodal HER2 heterogeneity at low protein expression levels (presence of HER2 0, HER2 1+, and/or HER2 2+ metastatic deposits within the same axilla) was seen in 40% (17/43) of cases. We found no statistically significant association between HER2 heterogeneity and other tumor-related parameters. Survival data indicated worse outcomes in the HER2-low group compared with the rest of the cohort. Conclusion: Our results indicate a substantial inst

Objective: HER2 status in breast cancer is an essential parameter in individual therapeutic decision-making and is routinely assessed in primary tumors in accordance with international recommendations. Reports of HER2 heterogeneity raise the question of basing treatment decisions on HER2 status in metastases, if present. We investigated the degree and clinical implications of HER2 heterogeneity in lymph node-positive breast cancer. Because of recent recognition of therapeutic opportunities in this group of tumors, we especially focused on cases involving low-level HER2 expression. Methods: The HER2 status of primary tumors and of corresponding lymph node metastases was determined in archived material at the protein and gene levels using the gene- protein assay and interpreted in accordance with 2018 ASCO/CAP criteria. HER2-low status was defined as protein expression levels 1+ or 2+ with negative amplification status. Results: We analyzed a series of 43 cases of primary infiltrating breast cancer, each with at least two axillary nodes harboring macrometastases (>2 mm), in total 206 such nodes. In 7% of cases, we detected intertumoral HER2 heterogeneity. Three of nine HER2-positive primary tumors were associated with HER2-negative metastases. No cases with HER2-negative primary tumors had HER2-positive metastases, but 55% (6/11) of HER2 0 primary tumors had HER2 1+ and/or 2+ metastases, and 19% (3/16) HER2 1+ cases had exclusively HER2 0 metastases. All metastases in HER2 2+ cases showed HER2-low protein expression levels. Internodal HER2 heterogeneity at low protein expression levels (presence of HER2 0, HER2 1+, and/or HER2 2+ metastatic deposits within the same axilla) was seen in 40% (17/43) of cases. We found no statistically significant association between HER2 heterogeneity and other tumor-related parameters. Survival data indicated worse outcomes in the HER2-low group compared with the rest of the cohort. Conclusion: Our results indicate a substantial inst

Current treatments for patients with metastatic triple negative breast cancer (TNBC) are generally ineffective. This manuscript shows for the first time that the survival of mice with metastatic TNBC can be markedly increased through dietary manipulation. Our study revealed that the survival of some mice with metastatic TNBC was increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) are manipulated, and the levels of lipids are markedly reduced. The anticancer activity of this non-pharmacological strategy was higher than that of drugs currently used in the treatment of patients with metastatic TNBC. This anticancer strategy also increased the survival of mice with other types of metastatic cancers. Manipulation of AA and lipid levels with artificial diets may be a useful strategy to treat patients with metastatic TNBC and other types of disseminated cancer., Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

11.7% of all cancer cases consist of breast cancer worldwide according to global cancer statistics. Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of common hormonal receptors - estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Due to this, TNBC is insensitive to endocrine or molecular targeted therapy and chemotherapy is the most effective treatment. Additionally, TNBC patients have reoccurrence within 3 years of diagnosis. Going further, due to the non-specific targeting of chemotherapy, cancer cells can develop drug resistance. The gold standard does not work in conjunction with microenvironmental factors to reduce disease progression and drug resistance. Not only is this disease lacking in effective treatments but is associated with a health disparity being most prevalent in pre-menopausal and African American women. There is clearlya need to understand the mechanisms of TNBC metastasis because of the impact not only on women in general but on women in historically marginalized communities. A significant innovation in determining cancer treatment is the use of genomic sequencing to identify mutations associated with metastasis. However, tumor heterogeneity puts limitations on fully understanding genomic landscape of TNBC, a highly mutational disease, using sequencing. Further, even when mutations are identified they may not be targetable, or patients may not respond to treatments. While genomic sequencing can be beneficial in improving treatment outcomes, they require further downstream validation of genetic expression to completely understand tumor biology and metastatic progression. This is where understanding the functional behavior of tumor cells with respect to their preferred secondary microenvironment can be advantageous in supplementing genomics data to get a comprehensive understanding of TNBC metastasis. The overall goal of this dissertation is to address th

Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (MAPK) pathway. A role for non-mutated Raf in metastasis is also emerging, but the driving mechanisms remain unclear. Elevated expression of any of the three wildtype Raf family members (C, A or B) can drive metastasis. Here, we utilized an in vivo model to show that wildtype C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage dependent manner. Analysis of the transcriptomic and phospho-proteomic landscape indicated that C-Raf driven metastasis is accompanied by upregulated MAPK signaling. Use of C-Raf mutants demonstrated that the dimerization domain, but not its kinase activity is essential for metastasis. Endogenous Raf monomer knockouts revealed C-Raf’s ability to form heterodimers with A-Raf and B-Raf are important for promoting metastasis. Taken together, these data identify wildtype C-Raf heterodimer signaling as a potential target for treating metastatic disease.

Chordoma is an uncommon, indolent malignant tumor arising from notochordal remnants. The incidence of distant metastasis varies between 30 and 40% in different series. Even though local involvement of the skin by direct invasion of chordoma is common, distant skin metastasis are rare, with less than 30 cases reported in the literature. The present clinical case illustrates the slow-growing natural history of a sacral chordoma, which evolved with lung metastasis, followed three years later by skin metastasis, thus giving us the opportunity to review the diagnostic approach, as well as the clinical and histopathological characteristics of this rare tumor.

During this course, we will study the similarities between cancer and normal development to understand how tumors co-opt normal developmental processes to facilitate cancer initiation, maintenance and progression. We will examine critical signaling pathways that govern these processes and, importantly, how some of these pathways hold promise as therapeutic targets for cancer treatment. We will discuss how future treatments might be personalized to target cancer cells in specific patients. We will also consider examples of newly-approved drugs that have dramatically helped patients combat this devastating disease. This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

Bone metastasis resulting from advanced breast cancer causes osteolysis and increases mortality in patients. Kalkitoxin (KT), a lipopeptide toxin derived from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), has an anti-metastatic effect on cancer cells. We verified that KT suppressed cancer cell migration and invasion in vitro and in animal models in the present study. We confirmed that KT suppressed osteoclast-soup-derived MDA-MB-231 cell invasion in vitro and induced osteolysis in a mouse model, possibly enhancing/inhibiting metastasis markers. Furthermore, KT inhibits CXCL5 and CXCR2 expression, suppressing the secondary growth of breast cancer cells on the bone, brain, and lungs. The breast-cancer-induced osteolysis in the mouse model further reveals that KT plays a protective role, judging by micro-computed tomography and immunohistochemistry. We report for the first time the novel suppressive effects of KT on cancer cell migration and invasion in vitro and on MDA-MB-231-induced bone loss in vivo. These results suggest that KT may be a potential therapeutic drug for the treatment of breast cancer metastasis.

BackgroundIn light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis.MethodsVangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model.ResultsWe observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics.ConclusionsWe conclude that Vangl-dependent Wnt/PCP signaling prom

Long non-coding RNAs (LncRNAs) are mRNA-like molecules that do not encode for proteins and that are longer than 200 nucleotides. LncRNAs play important biological roles in normal cell physiology and organism development. Therefore, deregulation of their activities is involved in disease processes such as cancer. Lung cancer is the leading cause of cancer-related deaths due to late stage at diagnosis, distant metastasis, and high rates of therapeutic failure. LncRNAs are emerging as important molecules in lung cancer for their oncogenic or tumor-suppressive functions. LncRNAs are highly stable in circulation, presenting an opportunity for use as non-invasive and early-stage cancer diagnostic tools. Here, we summarize the latest works providing in vivo evidence available for lncRNAs role in cancer development, therapy-induced resistance, and their potential as biomarkers for diagnosis and prognosis, with a focus on lung cancer. Additionally, we discuss current therapeutic approaches to target lncRNAs. The evidence discussed here strongly suggests that investigation of lncRNAs in lung cancer in addition to protein-coding genes will provide a holistic view of molecular mechanisms of cancer initiation, development, and progression, and could open up a new avenue for cancer treatment.

Cancer is one of the leading causes of mortality worldwide. Numerous strategies have been developed for cancer treatment. Metastasis, heterogeneity, chemotherapy resistance, recurrence, and evasion of immune surveillance are the primary reasons for the failure of cancer treatment. Cancer stem cells (CSCs) can give rise to tumors via self-renewal and differentiation into various cell types. They show resistance to chemotherapy and radiotherapy and have a strong capability of invasion and metastasis. Extracellular vesicles (EVs) are bilayered vesicles that carry biological molecules and are released under both healthy and unhealthy conditions. It has been shown that one of the leading causes of cancer treatment failure is cancer stem cell-derived EVs (CSC-EVs). CSC-EVs have essential roles in tumor progression, metastasis, tumor angiogenesis, chemoresistance, and immunosuppressants. In the future, controlling EV production in CSCs may be one of the most promising strategies to stop cancer treatment failures.

Introduction: The small intestine is the most frequent site of metastatic melanoma. However, its diagnosis continues to be a challenge since it is usually asymptomatic or with non-specific symptoms.Few cases result in complications, peritonitis due to perforation being infrequent. The objective of the work is to report a clinical case of peritonitis due to perforation of a melanoma metastasis in the small intestine. Clinical case: A 66-year-old male patient diagnosed with melanoma of the neck and secondary bone, brain and lung melanoma, underwent emergency surgery for acute peritonitis due to perforation of metastasis in the small intestine, which was resected and anastomosed. The histology confirmed the secondary nature of the cutaneous melanoma. Conclusion: Knowing that the jejunum-ileum is the most frequent site of melanoma metastases, in the presence of non-specific digestive symptoms or anemia, its involvement should be suspected and possible therapeutic alternatives should be evaluated., Introdução: O intestino delgado é o local mais frequente de melanoma metastático.O diagnóstico é um desafio por ser assintomático ou apresentar sintomas inespecíficos.Há poucos casos que apresentam complicações, sendo pouco frequente a peritonite por perfuração.O objetivo deste trabalho é relatar um caso clínico de peritonite por perfuração de metástase de melanoma no intestino delgado. Caso clínico: Paciente do sexo masculino, 66 anos, diagnosticado com melanoma no pescoço com metástase óssea, cefálica e pulmonar. Foi submetido a cirurgia de emergência por peritonite aguda por perfuração de metástases do intestino delgado. O estudo histológico confirmou melanoma cutâneo. Conclusão: Sabendo que o jejuno e o íleo é o local mais frequente de metástase de melanoma, na presença de sintomas digestivos inespecíficos ou anemia deve-se suspeitar de seu acometimento e avaliar possíveis alternativas terapêuticas., Introducción: El intestino delgado es el sitio de asiento más frecuente del melanoma metastásico. Su diagnóstico es un desafío por cursar asintomático o con síntomas inespecíficos. Son pocos los casos que presentan complicaciones, siendo infrecuente la peritonitis por perforación. El objetivo del trabajo es comunicar el caso clínico de una peritonitis por perforación de una metástasis de melanoma en intestino delgado. Caso clínico: Paciente de sexo masculino de 66 años con diagnóstico de melanoma de cuello y secundario óseo, encefálico y pulmonar, fue intervenido de urgencia por peritonitis aguda por perforación de metástasis en intestino delgado. El estudio histológico confirmó secundarismo de melanoma cutáneo. Conclusión: Sabiendo que el yeyuno íleon es el sitio de asiento más frecuente de las metástasis de melanoma, ante la presencia de síntomas digestivos inespecíficos o anemia se debe sospechar su compromiso y evaluar posibles alternativas terapéuticas.

The capacity of cells to adhere to, exert forces upon and migrate through their surrounding environment governs tissue regeneration and cancer metastasis. The role of the physical contractile forces that cells exert in this process, and the underlying molecular mechanisms are not fully understood. We, therefore, aimed to clarify if the extracellular forces that cells exert on their environment and/or the intracellular forces that deform the cell nucleus, and the link between these forces, are defective in transformed and invasive fibroblasts, and to indicate the underlying molecular mechanism of control. Confocal, Epifluorescence and Traction force microscopy, followed by computational analysis, showed an increased maximum contractile force that cells apply on their environment and a decreased intracellular force on the cell nucleus in the invasive fibroblasts, as compared to normal control cells. Loss of HDAC6 activity by tubacin-treatment and siRNA-mediated HDAC6 knockdown also reversed the reduced size and more circular shape and defective migration of the transformed and invasive cells to normal. However, only tubacin-mediated, and not siRNA knockdown reversed the increased force of the invasive cells on their surrounding environment to normal, with no effects on nuclear forces. We observed that the forces on the environment and the nucleus were weakly positively correlated, with the exception of HDAC6 siRNA-treated cells, in which the correlation was weakly negative. The transformed and invasive fibroblasts showed an increased number and smaller cell-matrix adhesions than control, and neither tubacin-treatment, nor HDAC6 knockdown reversed this phenotype to normal, but instead increased it further. This highlights the possibility that the control of contractile force requires separate functions of HDAC6, than the control of cell adhesions, spreading and shape. These data are consistent with the possibility that defective force-transduction from the extracellula, QC 20230824

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

Objective: HER2 status in breast cancer is an essential parameter in individual therapeutic decision-making and is routinely assessed in primary tumors in accordance with international recommendations. Reports of HER2 heterogeneity raise the question of basing treatment decisions on HER2 status in metastases, if present. We investigated the degree and clinical implications of HER2 heterogeneity in lymph node-positive breast cancer. Because of recent recognition of therapeutic opportunities in this group of tumors, we especially focused on cases involving low-level HER2 expression. Methods: The HER2 status of primary tumors and of corresponding lymph node metastases was determined in archived material at the protein and gene levels using the gene- protein assay and interpreted in accordance with 2018 ASCO/CAP criteria. HER2-low status was defined as protein expression levels 1+ or 2+ with negative amplification status. Results: We analyzed a series of 43 cases of primary infiltrating breast cancer, each with at least two axillary nodes harboring macrometastases (>2 mm), in total 206 such nodes. In 7% of cases, we detected intertumoral HER2 heterogeneity. Three of nine HER2-positive primary tumors were associated with HER2-negative metastases. No cases with HER2-negative primary tumors had HER2-positive metastases, but 55% (6/11) of HER2 0 primary tumors had HER2 1+ and/or 2+ metastases, and 19% (3/16) HER2 1+ cases had exclusively HER2 0 metastases. All metastases in HER2 2+ cases showed HER2-low protein expression levels. Internodal HER2 heterogeneity at low protein expression levels (presence of HER2 0, HER2 1+, and/or HER2 2+ metastatic deposits within the same axilla) was seen in 40% (17/43) of cases. We found no statistically significant association between HER2 heterogeneity and other tumor-related parameters. Survival data indicated worse outcomes in the HER2-low group compared with the rest of the cohort. Conclusion: Our results indicate a substantial inst

Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling - produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes - may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.

Breast cancer is the most prevalent cancer worldwide, and metastasis is the leading cause of death in cancer patients. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes. MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages (TAMs), and it became a candidate target of clinical intervention; however, the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1. The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues, including breast cancers. Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established. The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung, bone, and brain was examined in mouse breast cancer models. The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone. Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported. In the present manuscript, we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.

Magnetic resonance spectroscopy (MRS) is an MR technique that provides informa-tion about the biochemistry of tissues in a noninvasive way. MRS has been widelyused for the study of brain tumors, both preoperatively and during follow-up. In thisstudy, we investigated the performance of a range of variants of unsupervised matrixfactorization methods of the non-negative matrix underapproximation (NMU) family,namely, sparse NMU, global NMU, and recursive NMU, and compared them withconvex non-negative matrix factorization (C-NMF), which has previously shown agood performance on brain tumor diagnostic support problems using MRS data. Thepurpose of the investigation was 2-fold: first, to ascertain the differences among thesources extracted by these methods; and second, to compare the influence of eachmethod in the diagnostic accuracy of the classification of brain tumors, using them asfeature extractors. We discovered that, first, NMU variants found meaningful sourcesin terms of biological interpretability, but representing parts of the spectrum, incontrast to C-NMF; and second, that NMU methods achieved better classificationaccuracy than C-NMF for the classification tasks when one class was notmeningioma., H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions, grant number H2020-MSCA-ITN-2018-813120. Proyectos de investigación en salud 2020, grant numbers PI20/00064 and PI20/00360. Spanish Ministerio de Economía y Competitividad SAF2014-52332-R. AEI Research Project PID2019-104551RB-I00. Centro de Investigacion Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN [http://www.ciber-bbn.es/en, accessed on September 12, 2022], CB06/01/0010), an initiative of the Instituto de Salud Carlos III (Spain) co-funded by EU Fondo Europeo de Desarrollo Regional (FEDER). Spanish AEI PID2019-104551RB-I00 grant. XartecSalut, 2018 XARDI 00016 and 2021 XARDI 00021., Peer Reviewed, Postprint (published version)

Osteosarcoma is a rare malignant tumor that affects the bone. It has mesenchymal origin, and its incidence is higher during childhood and adolescence. In most cases, it develops in the metaphysis of long bones and clinically manifests with episodes of bone pain that may be accompanied by constitutional symptoms. It can be classified according to its grade, location and histological pattern; high-grade OS accounts for 90% of all cases and presents accelerated growth and grater aggressiveness. A bone biopsy is necessary to make a definitive diagnosis. Its definitive treatment includes surgery along with neoadjuvant and adjuvant chemotherapy, using the MAP regimen, which combines three chemotherapeutic agents and has proven to be the most effective, with an overall survival increase from 20% to 70%. Despite the efforts of the scientific community to develop new therapies that offer a better response, none of these has shown better results yet., El osteosarcoma (OS) es un tumor maligno infrecuente que afecta el hueso. Tiene origen mesenquimatoso y predomina en la infancia y adolescencia. Se localiza en la gran mayoría de los casos en metáfisis de huesos largos, y clínicamente debuta con episodios de dolor óseo que pueden estar o no acompañados de síntomas constitucionales. Se puede clasificar de acuerdo a su grado, localización y patrón histológico; el OS de alto grado abarca el 90% del total de casos y presenta crecimiento acelerado y mayor agresividad. Es necesaria una biopsia ósea para realizar el diagnóstico definitivo. Su tratamiento definitivo incluye la cirugía, en conjunto con quimioterapia neoadyuvante y adyuvante, mediante el esquema MAP, el cual combina tres quimioterapéuticos y ha demostrado ser el más eficaz, con un incremento de la sobrevida global de un 20% a un 70%. Pese al esfuerzo de la comunidad científica por desarrollar nuevas terapias que ofrezcan una mejor respuesta, ninguna de estas ha mostrado mejores resultados hasta el momento.

Loss of cell-cell adhesions is the indispensable first step for cancer cells to depart from the primary tumor mass to metastasize. Metastasis suppressor 1 (MTSS1) is frequently lost in metastatic tissues, correlating to advanced tumor stages and poor prognosis across a variety of cancers. Here we explore the anti-metastatic mechanisms of MTSS1, which have not been well understood. We found that MTSS1 is downregulated in NPC tissues. Lower levels of MTSS1 expression correlate to worse prognosis. We show that MTSS1 suppresses NPC cell migration and invasion in vitro through cytoskeletal remodeling at cell-cell borders and assembly of E-cadherin/beta-catenin/F-actin in adherens junctions. The I-BAR domain of MTSS1 was both necessary and sufficient to restore this formation of E-cadherin/beta-catenin/F-actin-mediated cell adherens junctions.

Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53−/− cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy.