Extracellular vesicles are a group of heterogeneous particles secreted during both physiological and pathological conditions which serve in intercellular communication and play a role in the development and progression of oral squamous cell carcinoma, the most common malignant tumor of the head and neck with a high mortality rate. Extensive research is being conducted in order to determine the precise role of extracellular vesicles in oncogenic processes and to explore the possible application of extracellular vesicles as early tumor biomarkers. In this review, we aimed to systematize observed roles extracellular vesicles might play in organizing of tumor microenvironment, tumor invasion and metastasis, as well as the impact of extracellular vesicles on immune dysregulation and development of resistance to chemotherapeutics. Additionally, we summarized findings involving the potential use of extracellular vesicles cargo proteins as early disease biomarkers.

Epigenetic mechanisms play a crucial role in the normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of these processes can result in changes to gene function and the transformation of cells into a malignant state. Cancer is characterized by widespread alterations in the epigenetic landscape, revealing that it involves not only genetic mutations but also epigenetic abnormalities. Recent progress in the field of cancer epigenetics has demonstrated significant reprogramming of various components of the epigenetic machinery in cancer, such as DNA methylation, modifications to histones, positioning of nucleosomes, and the expression of non-coding RNAs, particularly microRNAs. The ability to reverse epigenetic abnormalities has given rise to the hopeful field of epigenetic therapy, which has shown advancement with the recent approval by the FDA of three drugs targeting epigenetic mechanisms for the treatment of cancer. In the present manuscript, a comprehensive review has been presented about the role of understanding the epigenetic link between cancer and mechanisms by which phytomedicine offers treatment avenues. Further, this review deciphers the significance of natural products in the identification of epigenetic therapeutics, the diversity of their molecular targets, the use of nanotechnology, and the creation of new strategies for overcoming the inherent clinical challenges associated with developing these drug leads.

Colorectal cancer (CRC) is a growing concern all over the world. There has been a concerted effort to identify natural bioactive compounds that can be used to prevent or overcome this condition. Tocotrienols (T3s) are a naturally occurring form of vitamin E known for various therapeutic effects, such as anticancer, antioxidant, neuroprotective, and anti-inflammatory activities. The literature evidence suggests that two T3 analogues, ie, gamma (γ)- and delta (δ)-T3, can modulate cancers via several cancer-related signaling pathways. The aim of this review was to compile and analyze the existing literature on the diverse anticancer mechanisms of γT3 and δT3 exhibited in CRC cells, to showcase the anticancer potential of T3s. Medline was searched for research articles on anticancer effects of γT3 and δT3 in CRC published in the past 2 decades. A total of 38 articles (26 cell-based, 9 animal studies, 2 randomized clinical trials, and 1 scoping review) that report anticancer effects of γT3 and δT3 in CRC were identified. The findings reported in those articles indicate that γT3 and δT3 inhibit the proliferation of CRC cells, induce cell cycle arrest and apoptosis, suppress metastasis, and produce synergistic anticancer effects when combined with well-established anticancer agents. There is preliminary evidence that shows that T3s affect telomerase functions and support anticancer immune responses. γT3 and δT3 have the potential for development as anticancer agents.

Tumor cells with organ-specific metastasis traits arise in primary lesions with substantial variations of local niche mechanics owing to intratumoral heterogeneity. However, the roles of mechanically heterogeneous primary tumor microenvironment in metastatic organotropism remain an enigma. This study reports that persistent priming in soft but not stiff niches that mimic primary tumor mechanical heterogeneity induces transcriptional reprogramming reminiscent of neuron and promotes the acquisition of brain metastatic potential. Soft-primed cells generate brain metastases in vivo through enhanced transendothelial migration across blood-brain barrier and brain colonization, which is further supported by the findings that tumor cells residing in local soft niches of primary xenografts exhibit brain metastatic tropism. Mechanistically, soft niches suppress cytoskeleton-nucleus-mediated mechanotransduction, which promotes histone deacetylase 3 activity. Inhibiting histone deacetylase 3 abolishes niche softness-induced brain metastatic ability. Collectively, this study uncovers a previously unappreciated role of local niche softness within primary tumors in brain metastasis, highlighting the significance of primary tumor mechanical heterogeneity in metastatic organotropism.

As one part of the innate immune response to external stimuli, chronic inflammation increases the risk of various cancers, and tumor-promoting inflammation is considered one of the enabling characteristics of cancer development. Recently, there has been growing evidence on the role of anti-inflammation therapy in cancer prevention and treatment. And researchers have already achieved several noteworthy outcomes. In the review, we explored the underlying mechanisms by which inflammation affects the occurrence and development of cancer. The pro- or anti-tumor effects of these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, and extracellular matrix are discussed. Since FDA-approved anti-inflammation drugs like aspirin show obvious anti-tumor effects, these drugs have unique advantages due to their relatively fewer side effects with long-term use compared to chemotherapy drugs. The characteristics make them promising candidates for cancer chemoprevention. Overall, this review discusses the role of these inflammatory molecules in carcinogenesis of cancer and new inflammation molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that have already been or are expected to be applied in clinical practice, as well as recent discoveries of the anti-tumor effect of non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. The advantages and disadvantages of their application in cancer chemoprevention are also discussed.

Cancer adhesion to the mesothelium is critical for peritoneal metastasis, but how metastatic cells adapt to the biomechanical microenvironment remains unclear. Our study demonstrates that highly metastatic (HM), but not non-metastatic, ovarian cancer cells selectively activate the peritoneal mesothelium. HM cells exert a stronger adhesive force on mesothelial cells via P-cadherin, an adhesion molecule abundant in late-stage tumors. Mechanical activation of P-cadherin enhances lipogenic gene expression and lipid content in HM cells through SREBP1. P-cadherin also induces glycolysis in the interacting mesothelium without affecting lipogenic activity, with the resulting lactate serving as a substrate for lipogenesis in HM cells. Nanodelivery of small interfering RNA (siRNA) targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. Moreover, increased fatty acid synthase levels in metastatic patient samples correlate with high P-cadherin expression, supporting enhanced de novo lipogenesis in the metastatic niche. This study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain metastasis.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

To prevent disease, it is of great importance to detect the critical point (pre-disease state) when the biological system abruptly transforms from normal to disease state. However, rapid and accurate pre-disease state detection is still a challenge when there is only a single sample available. The state transition of the biological system is driven by the variation in regulations between genes.

In this study, we propose a rapid single-sample pre-disease state-identifying method based on the change in gene expression ranking, which can reflect the coordinated shifts between genes, that is, S-PCR. The R codes of S-PCR can be accessed at https://github.com/ZhenshenBao/S-PCR.

This model-free method is validated by the successful identification of pre-disease state for both simulated and five real datasets. The functional analyses of the pre-disease state-related genes identified by S-PCR also demonstrate the effectiveness of this computational approach. Furthermore, the time efficiency of S-PCR is much better than that of its peers.

Hence, the proposed S-PCR approach holds immense potential for clinical applications in personalized disease diagnosis.

Cancer is a therapeutically challenging and genomically complicated disease. Pioneering studies have uncovered multifaceted aspects of cancer, ranging from intra- and inter-tumor heterogeneity, drug resistance, and genetic/epigenetic mutations. Loss of apoptosis is another critical aspect that makes cancer cells resistant to death. A substantial fraction of mechanistic information gleaned from cutting-edge studies has enabled researchers to develop near-to-complete resolution of the apoptotic pathway. Within the exciting frontiers of apoptosis, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has garnered phenomenal appreciation by interdisciplinary researchers principally because of its unique capability to target cancer cells. TRAIL-based monotherapies and combinatorial therapies have reached phase II and phase III clinical trials. Rapidly upgrading the list of clinical trials substantiates the clinically valuable role of TRAIL-based therapeutics in cancer therapy. However, there is a growing concern about the poor bioavailability and rapid clearance of TRAIL-based therapeutics. Excitingly, the charismatic field of nanotechnology offers solutions for different problems, and we have witnessed remarkable breakthroughs in the efficacy of TRAIL-based therapeutics using nanotechnological approaches. In this review, we have attempted to provide a summary about different nanotechnologically assisted delivery methods for TRAIL-based therapeutics in cell culture studies and animal model studies for the inhibition/prevention of cancer.

High-dose denosumab (Xgeva®) is increasingly used for treating bone metastasis and various malignant diseases but carries the risk of medication-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the incidence, risk factors, and clinical outcomes of MRONJ in patients treated with high-dose denosumab.

A retrospective review was performed on 1278 patients who received high-dose denosumab at Severance Hospital, Seoul, South Korea, from September 2014 to February 2023. Data on the incidence of MRONJ, patient demographics, primary diseases, and treatment outcomes were analyzed.

Among the 1278 patients (average age 64.72 years; 728 males and 550 females) treated, 34 developed MRONJ, with a 2.66% incidence rate. The average age of those with MRONJ was 68.32 years, and they received more Xgeva® injections on average (13.62) compared to the overall cohort. Factors such as age and the frequency of injections were significantly associated with the risk of MRONJ. Notably, the incidence of MRONJ did not significantly differ between those who underwent oral surgery and those with spontaneous MRONJ, especially if oral surgery occurred within 1 month of injection. Surgical interventions have shown higher recovery rates in advanced MRONJ stages.

This study confirmed a significant MRONJ incidence of 2.66% among high-dose denosumab recipients, highlighting the importance of careful patient selection, monitoring, and education, particularly in older and long-term treatment patients, to mitigate the risk of MRONJ.

Cathepsin L (CTSL), a cysteine cathepsin protease of the papain superfamily, plays a crucial role in cancer progression and metastasis. Dysregulation of CTSL is frequently observed in tumor malignancies, leading to the degradation of extracellular matrix and facilitating epithelial-mesenchymal transition (EMT), a key process in malignant cancer metastasis. This review mainly provides a comprehensive information about recent findings on natural inhibitors targeting CTSL and their anticancer effects, which have emerged as potent anticancer therapeutic agents or metastasis-suppressive adjuvants. Specifically, inhibitors are categorized into small-molecule and macromolecule inhibitors, with a particular emphasis on cathepsin propeptide-type macromolecules. Additionally, the article explores the molecular mechanisms of CTSL involvement in cancer metastasis, highlighting its regulation at transcriptional, translational, post-translational, and epigenetic levels. This work underscores the importance of understanding natural CTSL inhibitors and provides researchers with practical insights to advance the relevant fields and discover novel CTSL-targeting inhibitors from natural sources.

Bone metastasis, a frequent and detrimental complication of advanced cancers, often triggers bone deterioration events that severely compromise patient quality of life and prognosis. The past few years have witnessed the emergence and continuous advancements in immunotherapy, ushering in innovative therapeutic prospects for bone metastasis. These advancements include not only the use of immune checkpoint inhibitors (ICIs), both as standalone and combined treatments, but also the investigation of novel targets within immune cells residing in bone metastases. These breakthroughs have instilled fresh optimism for effectively managing patients with bone metastasis. This article endeavors to present an exhaustive review of the recent progress made across a spectrum of immunotherapeutic strategies and targeted therapies specifically designed for individuals battling bone metastasis from malignant tumors. By doing so, it seeks to offer insights that can inform clinical practices and guide further medical research in this domain.

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds, BY4003 and BY4008, were synthesized to target the JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC50 values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.

Metastasis is an intricate and formidable pathophysiological process encompassing the dissemination of cancer cells from the primary tumour body to distant organs. It stands as a profound and devastating phenomenon that constitutes the primary driver of cancer-related mortality. Despite great strides of advancements in cancer research and treatment, tailored anti-metastasis therapies are either lacking or have shown limited success, necessitating a deeper understanding of the intrinsic elements driving cancer invasiveness. This comprehensive review presents a contemporary elucidation of pivotal facets within the realm of cancer metastasis, commencing with the intricate processes of homing and invasion. The process of angiogenesis, which supports tumour growth and metastasis, is addressed, along with the pre-metastatic niche, wherein the primary tumour prepares for a favorable microenvironment at distant sites for subsequent metastatic colonization. The landscape of metastasis-related genetic and epigenetic mechanisms, involvement of metastasis genes and metastasis suppressor genes, and microRNAs (miRNA) are also discussed. Furthermore, immune modulators' impact on metastasis and their potential as therapeutic targets are addressed. The interplay between cancer cells and the immune system, including immune evasion mechanisms employed by metastatic cells, is discussed, highlighting the importance of targeting immune modulation in arresting metastatic progression. Finally, this review presents promising treatment opportunities derived from the insights gained into the mechanisms of metastasis. Identifying novel therapeutic targets and developing innovative strategies to disrupt the metastatic cascade holds excellent potential for improving patient outcomes and ultimately reducing cancer-related mortality.

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.

The pathologic evaluation and clinical course of cytoreductive nephrectomy after combined immuno-oncology therapy were reviewed to understand the benefits of cytoreductive nephrectomy.

Three patients with clear cell carcinoma underwent tumor biopsy before combined immuno-oncology therapy. Case 1 was found to have a sarcomatoid component upon nephrectomy and continued with combined immuno-oncology therapy. Case 2 discontinued combined immuno-oncology therapy due to adverse events but maintained tumor shrinkage. The patient was found to have viable cells in most nephrectomy specimens but has had no recurrence after combined immuno-oncology therapy was discontinued. In case 3, the residual tumor was deemed resectable with combined immuno-oncology therapy, and nephrectomy and metastasectomy were performed. No viable cells were observed in either specimen, and the patient has had no recurrence.

Cytoreductive nephrectomy after combined immuno-oncology therapy may be useful to allow pathologic evaluation of treatment and provide an indicator for subsequent treatment.

Receptor interacting protein serine/threonine kinase 4 (RIPK4) is widely involved in human cancer development. Nevertheless, its role in colon cancer (COAD) has not been elucidated till now. Our research aimed at exploring the function and underlying molecular mechanism of RIPK4 in COAD progression. Through bioinformatic analyses and RT-qPCR, RIPK4 was discovered to be increased in COAD cells and tissues, and its high level predicted poor prognosis. Loss-of-function assays revealed that RIPK4 silencing suppressed COAD cell growth, induced cell cycle arrest, and enhanced cell apoptosis. In vivo experiments also proved that tumor growth was inhibited by silencing of RIPK4. Luciferase reporter assay validated that RIPK4 was targeted and negatively regulated by miR-575. Western blotting demonstrated that Wnt3a, phosphorylated (p)-GSK-3β, and cytoplasmic and nuclear β-catenin protein levels, β-catenin nuclear translocation, and Cyclin D1, CDK4, Cyclin E, and c-Myc protein levels were reduced by RIPK4 knockdown, which however was reversed by treatment with LiCl, the Wnt/β-catenin pathway activator. LiCl also offset the influence of RIPK4 knockdown on COAD cell growth, cell cycle process, and apoptosis. Finally, RIPK4 downregulation reduced RUNX1 level, which was upregulated in COAD and its high level predicted poor prognosis. RIPK4 is positively associated with RUNX1 in COAD. Overexpressing RUNX1 antagonized the suppression of RIPK4 knockdown on RUNX1, Wnt3a, p-GSK-3β, cytoplasmic β-catenin, nuclear β-catenin, Cyclin D1, CDK4, Cyclin E, and c-Myc levels. Collectively, miR-575/RIPK4 axis repressed COAD progression via inactivating the Wnt/β-catenin pathway through downregulating RUNX1.

This research delves into the influence of H2Valdien derivatives on the proliferation, migration, and apoptosis induction in hepatoma carcinoma cells (HepG2, Huh-7, and SMMC-7721), with a specific emphasis on inhibiting epithelial-mesenchymal transition (EMT) through modulation of the Hedgehog (Hh) signaling pathway. Utilizing the cell counting kit-8 method, flow cytometry, TUNEL assay, wound healing, and transwell assays, we observed a dose-dependent growth arrest and apoptosis induction in HepG2, Huh-7, and SMMC-7721 cells. Notably, H2Valdien derivatives exhibited a capacity to reduce migration and invasion, impacting the expression of EMT-associated proteins such as N-cadherin, vimentin, and E-cadherin. Mechanistically, these derivatives demonstrated the inhibition of the Hh signaling pathway by inactivating Sonic Hh (Shh) and smoothened proteins. This study underscores the robust antiproliferative and apoptosis-inducing effects of H2Valdien derivatives on hepatoma carcinoma cells and elucidates their regulatory role in EMT through modulation of the Hh signaling pathway, providing valuable insights for potential therapeutic interventions.

Studies have identified genes and molecular pathways regulating cancer metastasis. However, it remains largely unknown whether metastatic potentials of cancer cells from different lineage types are driven by the same or different gene networks. Here, we aim to address this question through integrative analyses of 493 human cancer cells' transcriptomic profiles and their metastatic potentials in vivo. Using an unsupervised approach and considering both gene coexpression and protein-protein interaction networks, we identify different gene networks associated with various biological pathways (i.e. inflammation, cell cycle, and RNA translation), the expression of which are correlated with metastatic potentials across subsets of lineage types. By developing a regularized random forest regression model, we show that the combination of the gene module features expressed in the native cancer cells can predict their metastatic potentials with an overall Pearson correlation coefficient of 0.90. By analyzing transcriptomic profile data from cancer patients, we show that these networks are conserved in vivo and contribute to cancer aggressiveness. The intrinsic expression levels of these networks are correlated with drug sensitivity. Altogether, our study provides novel comparative insights into cancer cells' intrinsic gene networks mediating metastatic potentials across different lineage types, and our results can potentially be useful for designing personalized treatments for metastatic cancers.

Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival.

Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target.

In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression.

Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients.

WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as significant regulators of multiple pathways associated with cancer and other diseases, owing to their capacity to remove ubiquitin from target substrates and modulate signaling. Consequently, they represent potential therapeutic targets for cancer and other life-threatening conditions. USP43 belongs to the DUBs family involved in cancer development and progression. This review aims to provide a comprehensive overview of the existing scientific evidence implicating USP43 in cancer development. Additionally, it will investigate potential small-molecule inhibitors that target DUBs that may have the capability to function as anti-cancer medicines.

Disease progression in biosystems is not always a steady process but is occasionally abrupt. It is important but challenging to signal critical transitions in complex biosystems.

In this study, based on the theoretical framework of dynamic network biomarkers (DNBs), we propose a model-free method, edge-based relative entropy (ERE), to identify temporal key biomolecular associations/networks that may serve as DNBs and detect early-warning signals of the drastic state transition during disease progression in complex biological systems. Specifically, by combining gene‒gene interaction (edge) information with the relative entropy, the ERE method converts gene expression values into network entropy values, quantifying the dynamic change in a biomolecular network and indicating the qualitative shift in the system state.

The proposed method was validated using simulated data and real biological datasets of complex diseases. The applications show that for certain diseases, the ERE method helps to reveal so-called "dark genes" that are non-differentially expressed but with high ERE values and of essential importance in both gene regulation and prognosis.

The proposed method effectively identified the critical transition states of complex diseases at the network level. Our study not only identified the critical transition states of various cancers but also provided two types of new prognostic biomarkers, positive and negative edge biomarkers, for further practical application. The method in this study therefore has great potential in personalized disease diagnosis.

Surgery followed by adjuvant chemotherapy or radiation therapy remains the mainstream treatment for breast cancer in the clinic. However, cancer recurrence post surgery is still common. In view of the clinical practice that autologous fat tissue grafting is often used to facilitate breast reconstruction after lumpectomy, here we develop an in vivo targetable adipocyte-based drug depot for the prevention of post-surgical cancer recurrence. We show that primary adipocytes can be metabolically labeled with clickable chemical tags (e.g., azido groups), for subsequent conjugation of dibenzocyclooctyne (DBCO)-bearing cargo via efficient click chemistry. The conjugated cargo can retain well on the adipocyte membrane. By incorporating a cleavable linker between DBCO and cargo, the conjugated cargo can be gradually released from the surface of adipocytes to effect on neighboring cells. In the context of breast cancer surgery, azido-labeled adipocytes grafted to the surgical site can capture circulating DBCO-drugs for improved prevention of 4T1 triple-negative breast cancer (TNBC) recurrence and metastasis. This targetable and refillable adipocyte-based drug depot holds great promise for drug delivery, transplantation, and other applications.

The progression of metastasis, a complex systemic disease, is facilitated by interactions between tumor cells and their isolated microenvironments. Over the past few decades, researchers have investigated the metastatic spread of cancer extensively, identifying multiple stages in the process, such as intravasation, extravasation, tumor latency, and the development of micrometastasis and macrometastasis. The premetastatic niche is established in target organs by the accumulation of aberrant immune cells and extracellular matrix proteins. The "seed and soil" idea, which has become widely known and accepted, is being used to this day to guide cancer studies. Changes in the local and systemic immune systems have a major impact on whether an infection spreads or not. The belief that the immune response may play a role in slowing tumor growth and may be beneficial against the metastatic disease underpins the responsiveness shown in the immunological landscape of metastasis. Various hypotheses on the phylogenesis of metastases have been proposed in the past. The primary tumor's secreting factors shape the intratumoral microenvironment and the immune landscape, allowing this progress to be made. Therefore, it is evident that among disseminated tumor cells, there are distinct phenotypes that either carry budding for metastasis or have the ability to obtain this potential or in systemic priming through contact with substantial metastatic niches that have implications for medicinal chemistry. Concurrent immunity signals that the main tumor induces an immune response that may not be strong enough to eradicate the tumor. Immunotherapy's success with some cancer patients shows that it is possible to effectively destroy even advanced-stage tumors by modifying the microenvironment and tumor-immune cell interactions. This review focuses on the metastasome in colorectal carcinoma and the therapeutic implications of site-specific metastasis, systemic priming, tumor spread, and the relationship between the immune system and metastasis.

Metastasis is a significant clinical challenge responsible for cancer mortality and non-response to treatment. However, the molecular mechanisms driving metastasis remain unclear, limiting the development of efficient diagnostic and therapeutic approaches. Recent breakthroughs in cancer biology have discovered a group of small non-coding RNAs called tRNA-derived fragments (tRFs), which play a critical role in the metastatic behavior of various tumors. tRFs are produced from cleavage modifications of tRNAs and have different functional classes based on the pattern of these modifications. They perform post-transcriptional regulation through microRNA-like functions, displacing RNA-binding proteins, and play a role in translational regulation by inducing ribosome synthesis, translation initiation, and epigenetic regulation. Tumor cells manipulate tRFs to develop and survive the tumor mass, primarily by inducing metastasis. Multiple studies have demonstrated the potential of tRFs as therapeutic, diagnostic, and prognostic targets for tumor metastasis. This review discusses the production and function of tRFs in cells, their aberrant molecular contributions to the metastatic environment, and their potential as promising targets for anti-metastasis treatment strategies.

Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients.

A case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing -log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation.

Glycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 (HAX1) and hyaluronan-mediatedmotility receptor (HMMR), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis.

Combining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC.

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.

Cancer is a leading cause of mortality in humans, but the efficacy of current treatments for many cancers is limited, as they lack unique mechanistically defined targets. Here, we show that, upon malignant transformation, aggressive oncocells generate a second membrane exterior to their plasma membrane to form cytocapsulas (CCs) and cytocapsular tubes (CCTs), which all together constitute cytocapsular oncocells with pleotropic biological functions in cancer patient tissues in vivo. Proteomic and biochemical analyses revealed that the PMCA2 calcium pump is highly up-regulated in CCs and CCTs in malignant tumors but not in normal tissues, thus identifying a unique cancer biomarker and target for cancer therapy. Cytocapsular oncocells are universally present in solid cancers and appear in hematologic cancers in immune organs. Multi-cell malignant tumors are also enveloped by protective CC membranes. These cytocapsular tumors (CTs) generate numerous CCTs that form freeways for cancer cell metastasis to both neighboring and distant destinations. Entire cytocapsular tumor networks (CTNs) dominate physical cancer metastasis pathways in cancer patients in vivo. Later, CCTs invade micro blood vessels and release cytocapsular oncocells into the blood, providing a source of circulating tumor cells. CTNs interconnect cytocapsular tumors in primary and secondary cancer niches, creating larger cytocapsular tumor network systems (CTNSs). Primary and secondary CTNSs are in turn interconnected, forming dynamic and integrated CTNSs. Thus, interconnected cytocapsular oncocells, CTNs, and CTNSs coordinate cancer progression via the integrated cytocapsular membrane systems.

Metastatic cancer is a major cause of cancer-related mortality; however, the complex regulation process remains to be further elucidated. A large amount of preliminary investigations focus on the role of epigenetic mechanisms in cancer metastasis. Notably, the posttranslational modifications were found to be critically involved in malignancy, thus attracting considerable attention. Beyond acetylation, novel forms of acylation have been recently identified following advances in mass spectrometry, proteomics technologies, and bioinformatics, such as propionylation, butyrylation, malonylation, succinylation, crotonylation, 2-hydroxyisobutyrylation, lactylation, among others. These novel acylations play pivotal roles in regulating different aspects of energy mechanism and mediating signal transduction by covalently modifying histone or nonhistone proteins. Furthermore, these acylations and their modifying enzymes show promise regarding the diagnosis and treatment of tumors, especially tumor metastasis. Here, we comprehensively review the identification and characterization of 11 novel acylations, and the corresponding modifying enzymes, highlighting their significance for tumor metastasis. We also focus on their potential application as clinical therapeutic targets and diagnostic predictors, discussing the current obstacles and future research prospects.

About 20%-30% of breast cancer (BC) patients will develop distant metastases, preferentially in bones, liver, lung, and brain. BCs with different intrinsic subtypes prefer different sites for metastasis. These subtypes vary in the abundance of genetic alterations which may influence the localization of metastases. Currently, information about the relation between metastatic site and mutational profile of BC is limited. In this study, n = 521 BC metastases of the most frequently affected sites (bone, brain, liver, and lung) were investigated for the frequency of AKT1, ERBB2, ESR1, PIK3CA, and TP53 mutations via NGS and pyrosequencing. Somatic mutations were present in 64% cases. PIK3CA and TP53 were the most frequently mutated genes under study. We provide an analysis of the mutational profile of BCs and the affected metastatic site. Genetic alterations differed significantly depending on the organ site affected by metastases. TP53 mutations were mostly observed in brain metastases (51.0%), metastases outside of the brain revealed a much lower proportion of TP53 mutated samples. PIK3CA mutations are frequent in liver (40.6%), lung (36.8%), and bone metastases (35.7%), whereas less common in brain metastases (18.4%). The highest percentage of ESR1 mutations was observed in liver and lung metastases (about 30% each), whereas metastatic lesions in the brain showed significantly less ESR1 mutations, only in 2.0% of the cases. In summary, we found significant differences of mutational status in mBC depending on the affected organ and intrinsic subtype. Organotropism of metastatic cancer spread may be influenced by the mutational profile of individual BCs.

The ubiquitin-proteasome system (UPS) is a fundamental regulatory mechanism in cells, vital for maintaining cellular homeostasis, compiling signaling transduction, and determining cell fates. These biological processes require the coordinated signal cascades of UPS members, including ubiquitin ligases, ubiquitin-conjugating enzymes, deubiquitinases, and proteasomes, to ubiquitination and de-ubiquitination on substrates. Recent studies indicate that ubiquitination code rewriting is particularly prominent in pancreatic cancer. High frequency mutation or aberrant hyperexpression of UPS members dysregulates ferroptosis, tumor microenvironment, and metabolic rewiring processes and contribute to tumor growth, metastasis, immune evasion, and acquired drug resistance. We conduct an in-depth overview of ubiquitination process in pancreatic cancer, highlighting the role of ubiquitin code in tumor-promoting and tumor-suppressor pathways. Furthermore, we review current UPS modulators and analyze the potential of UPS modulators as cancer therapy.

Sorghum is a gluten-free cereal commonly used in foods, and its consumption has been associated with the prevention of human chronic conditions such as obesity and cancer, due to the presence of dietary fiber and phenolic compounds. This study aimed to evaluate, for the first time, the antiproliferative, antioxidant, anti-adhesion, anti-invasion, and antimalarial activities of phenolic extracts from toasted white and tannin sorghum flours to understand how different phenolic profiles contribute to sorghum biological activities. Water and 70 % ethanol/water (v/v), eco-friendly solvents, were used to obtain the phenolic extracts of toasted sorghum flours, and their phenolic profile was analyzed by UPLC-MSE. One hundred forty-five (145) phenolic compounds were identified, with 23 compounds common to all extracts. The solvent type affected the phenolic composition, with aqueous extract of both white sorghum (WSA) and tannin sorghum (TSA) containing mainly phenolic acids. White sorghum (WSE) and tannin sorghum (TSE) ethanolic extracts exhibited a higher abundance of flavonoids. WSE demonstrated the lowest IC50 on EA.hy926 (IC50 = 46.6 µg/mL) and A549 cancer cells (IC50 = 33.1 µg/mL), while TSE showed the lowest IC50 (IC50 = 70.8 µg/mL) on HCT-8 cells (human colon carcinoma). Aqueous extracts also demonstrated interesting results, similar to TSE, showing selectivity for cancer cells at higher IC50 concentrations. All sorghum extracts also reduced the adhesion and invasion of HCT-8 cells, suggesting antimetastatic potential. WSE, rich in phenolic acids and flavonoids, exhibited greater toxicity to both the W2 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains of Plasmodium falciparum (IC50 = 8 µg GAE/mL and 22.9 µg GAE/mL, respectively). These findings underscore the potential health benefits of toasted sorghum flours, suggesting diverse applications in the food industry as a functional ingredient or even as an antioxidant supplement. Moreover, it is suggested that, besides the phenolic concentration, the phenolic profile is important to understand the health benefits of sorghum flours.

Postoperative distant metastasis is the main cause of death in breast cancer patients. We aimed to construct a nomogram to predict the risk of metastasis of luminal B type invasive ductal carcinoma.

We applied the data of 364 luminal B type breast cancer patients between 2008 and 2013. Patients were categorized into modeling group and validation group randomly (1:1). The breast cancer metastasis nomogram was developed from the logistic regression model using clinicopathological variables. The area under the receiver-operating characteristic curve (AUC) was calculated in modeling group and validation group to evaluate the predictive accuracy of the nomogram.

The multivariate logistic regression analysis showed that tumor size, No. of the positive level 1 axillary lymph nodes, human epidermal growth factor receptor 2 (HER2) status and Ki67 index were the independent predictors of the breast cancer metastasis. The AUC values of the modeling group and the validation group were 0.855 and 0.818, respectively. The nomogram had a well-fitted calibration curve. The positive and negative predictive values were 49.3% and 92.7% in the modeling group, and 47.9% and 91.0% in the validation group. Patients who had a score of 60 or more were thought to have a high risk of breast cancer metastasis.

The nomogram has a great predictive accuracy of predicting the risk of breast cancer metastasis. If patients had a score of 60 or more, necessary measures, like more standard treatment methods and higher treatment adherence of patients, are needed to take to lower the risk of metastasis and improve the prognosis.

Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling. TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.