Metastatic Potential Research Articles

Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.

Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer. The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice. GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1. Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2.

Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood. In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques. Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model. Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

Decreased Lung Metastasis in Triple Negative Breast Cancer Following Locally Delivered Supratherapeutic Paclitaxel-Loaded Polyglycerol Carbonate Nanoparticle Therapy.

Breast cancer is among the most prevalent malignancies, accounting for 685,000 deaths worldwide in 2020, largely due to its high metastatic potential. Depending on the stage and tumor characteristics, treatment involves surgery, chemotherapy, targeted biologics, and/or radiation therapy. However, current treatments are insufficient for treating or preventing metastatic disease. Herein, we describe supratherapeutic paclitaxel-loaded nanoparticles (81 wt % paclitaxel) to treat the primary tumor and reduce the risk of subsequent metastatic lesions in the lungs. Primary tumor volume and lung metastasis are reduced by day 30, compared to the paclitaxel clinical standard treatment. The ultrahigh levels of paclitaxel afford an immunotherapeutic effect, increasing natural killer cell activation and decreasing NETosis in the lung, which limits the formation of metastatic lesions.

Tongue Metastasis From Renal Cell Carcinoma: A Rare Case Presentation.

Renal cell carcinoma (RCC) is characterized by a marked metastatic potential and is the third most common cancer of metastasis to the head and neck, following breast and lung cancer. We report a rare case of a patient with RCC with metastasis to the tongue. A 72-year-old man visited our otorhinolaryngology clinic complaining of tongue pain and ulcerative lesions which occurred 3 weeks before. The patient had been diagnosed with RCC and received a right radical nephrectomy 3 years previously. Because the lesion was suspected to be malignant, a hemiglossectomy was planned. However, metastatic lesions were suspected on the left upper lung and the left 10th ribs in imaging studies and the result of an incisional biopsy revealed tongue metastasis of RCC. RCC metastasis to the tongue is extremely rare. Only 51 cases were reported worldwide from 1911 to 2017. According to the literature, no case of RCC metastasis to the tongue has been reported to date in Korea. Therefore, we report this case along with a review of the literature.

Hsa_circ_0005397 promotes hepatocellular carcinoma progression through EIF4A3

PurposeThe purpose of this study was to explore the expression and potential mechanism of hsa_circ_0005397 in hepatocellular carcinoma progression.MethodsQuantitative reverse transcription-polymerase chain reaction(qRT-PCR) was used to measure the expression level of hsa_circ_0005397 and EIF4A3 from paired HCC tissues and cell lines. Western Blot (WB) and immunohistochemistry (IHC) were used to verify the protein level of EIF4A3. The specificity of primers was confirmed by agarose gel electrophoresis. Receiver Operating Characteristic (ROC) Curve was drawn to analyze diagnostic value. Actinomycin D and nuclear and cytoplasmic extraction assays were utilized to evaluate the characteristics of hsa_circ_0005397. Cell Counting kit-8 (CCK-8) and colony formation assays were performed to detect cell proliferation. Flow cytometry analysis was used to detect the cell cycle. Transwell assay was performed to determine migration and invasion ability. RNA-binding proteins (RBPs) of hsa_circ_0005397 in HCC were explored using bioinformatics websites. The relationship between hsa_circ_0005397 and Eukaryotic Translation Initiation Factor 4A3 (EIF4A3) was verified by RNA Binding Protein Immunoprecipitation (RIP) assays, correlation and rescue experiments.ResultsIn this study, hsa_circ_0005397 was found to be significantly upregulated in HCC, and the good diagnostic sensitivity and specificity shown a potential diagnostic capability. Upregulated expression of hsa_circ_0005397 was significantly related to tumor size and stage. Hsa_circ_0005397 was circular structure which more stable than liner mRNA, and mostly distributed in the cytoplasm. Upregulation of hsa_circ_0005397 generally resulted in stronger proliferative ability, clonality, and metastatic potency of HCC cells; its downregulation yielded the opposite results. EIF4A3 is an RNA-binding protein of hsa_circ_0005397, which overexpressed in paired HCC tissues and cell lines. In addition, expression of hsa_circ_0005397 decreased equally when EIF4A3 was depleted. RIP assays and correlation assay estimated that EIF4A3 could interacted with hsa_circ_0005397. Knockdown of EIF4A3 could reverse hsa_circ_0005397 function in HCC progression.ConclusionsHsa_circ_0005397 promotes progression of hepatocellular carcinoma through EIF4A3. These research findings may provide novel clinical value for hepatocellular carcinoma.

Molecular panorama of therapy resistance in prostate cancer: a pre-clinical and bioinformatics analysis for clinical translation.

Prostate cancer (PCa) is a malignant disorder of prostate gland being asymptomatic in early stages and high metastatic potential in advanced stages. The chemotherapy and surgical resection have provided favourable prognosis of PCa patients, but advanced and aggressive forms of PCa including CRPC and AVPC lack response to therapy properly, and therefore, prognosis of patients is deteriorated. At the advanced stages, PCa cells do not respond to chemotherapy and radiotherapy in a satisfactory level, and therefore, therapy resistance is emerged. Molecular profile analysis of PCa cells reveals the apoptosis suppression, pro-survival autophagy induction, and EMT induction as factors in escalating malignant of cancer cells and development of therapy resistance. The dysregulation in molecular profile of PCa including upregulation of STAT3 and PI3K/Akt, downregulation of STAT3, and aberrant expression of non-coding RNAs are determining factor for response of cancer cells to chemotherapy. Because of prevalence of drug resistance in PCa, combination therapy including co-utilization of anti-cancer drugs and nanotherapeutic approaches has been suggested in PCa therapy. As a result of increase in DNA damage repair, PCa cells induce radioresistance and RelB overexpression prevents irradiation-mediated cell death. Similar to chemotherapy, nanomaterials are promising for promoting radiosensitivity through delivery of cargo, improving accumulation in PCa cells, and targeting survival-related pathways. In respect to emergence of immunotherapy as a new tool in PCa suppression, tumour cells are able to increase PD-L1 expression and inactivate NK cells in mediating immune evasion. The bioinformatics analysis for evaluation of drug resistance-related genes has been performed.

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

Human osteosarcoma (OS) is a relatively rare malignancy preferentially affecting long body bones which prognosis is often poor also due to the lack of effective therapies. Clinical management of this cancer basically relies on surgical removal of primary tumor coupled with radio/chemotherapy. Unfortunately, most osteosarcoma cells are resistant to conventional therapy, with the undergoing epithelial-mesenchymal transition (EMT) giving rise to gene expression reprogramming, thus increasing cancer cell invasiveness and metastatic potential. Alternative clinical approaches are thus urgently needed. In this context, the recently described ferroptotic cell death represents an attractive new strategy to efficiently kill cancer cells, since most chemoresistant and mesenchymal-shaped tumors display high susceptibility to pro-ferroptotic compounds. However, cancer cells have also evolved anti-ferroptotic strategies, which somehow sustain their survival upon ferroptosis induction. Indeed, here we show that osteosarcoma cell lines display heterogeneous sensitivity to ferroptosis execution, correlating with the mesenchymal phenotype, which is consistently affected by the expression of the well-known anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1). Interestingly, inhibiting the activity or expression of FSP1 restores cancer cell sensitivity to ferroptosis. Moreover, we also found that: i) AKRs might also contribute to resistance; ii) NRF2 enhances FSP1 expression upon ferroptosis induction; while iii) p53 contributes to the regulation of FSP1 basal expression in OS cells.In conclusion, FSP1 expression can potentially be used as a valuable predictive marker of OS sensitivity to ferroptosis and as a new potential therapeutic target.

CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid β-oxidation in triple-negative breast cancer

CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. Comprehensive in silico gene expression analysis of breast tumors followed by lipidomic and metabolomic analyses of CD24-modulated cells revealed that CD24 negativity induces mitochondrial oxidative phosphorylation and reprograms TNBC metabolism toward the fatty acid beta-oxidation (FAO) pathway. CD24 silencing activates PPARα-mediated regulation of FAO in TNBC cells. Further analysis using reverse-phase protein array and its validation using CD24-modulated TNBC cells and xenograft models nominated CD24-NF-κB-CPT1A signaling pathway as the central regulatory mechanism of CD24-mediated FAO activity. Overall, our study proposes a novel role of CD24 in metabolic reprogramming that can open new avenues for the treatment strategies for patients with metastatic TNBC.

Comprehensive Review on Pancreatic Head Cancer: Pathogenesis, Diagnosis, and Treatment Challenges in the Quest for Improved Survival.

This comprehensive review explores the complexities surrounding pancreatic head cancer, a highly fatal and challenging-to-treat illness with a survival rate of less than five years. Despite being a major contributor to cancer-related deaths, pancreatic head malignancy often eludes early detection due to its posterior location and high metastatic potential. The review delves into the associated symptoms, including gastric outlet obstruction and obstructive jaundice, highlighting the impact on the patient's eligibility for surgery. Examining recent advancements, the article discusses fast-track surgery recovery programs and emerging immunotherapeutic approaches, acknowledging the unique challenges posed by the immunosuppressive environment of pancreatic head cancer. Additionally, the review elucidates the intricate relationship between pancreatic cancer and glucose levels, emphasizing the role of islets of Langerhans in insulin production. The pathogenesis section explores lifestyle and genetic factors contributing to pancreatic head carcinoma, shedding light on risk factors such as smoking, obesity, diabetes, and hereditary predispositions. The extensive analysis of pancreatic cancer diagnosis methods encompasses imaging techniques, biopsies, and biomarkers, emphasizing the challenges posed by late-stage diagnoses. Addressing treatment modalities, the review emphasizes the significance of surgery, chemotherapy, radiotherapy, and targeted therapy. The intricate details of neoadjuvant, immunotherapy, and microbial therapy provide a comprehensive understanding of evolving treatment strategies. The review concludes by highlighting promising areas of research, including oncolytic viral therapy and gene editing technology, aiming to enhance the limited treatment options for this devastating disease.

The evolving management of small renal masses.

Small renal masses (SRMs) are a heterogeneous group of tumours with varying metastatic potential. The increasing use and improving quality of abdominal imaging have led to increasingly early diagnosis of incidental SRMs that are asymptomatic and organ confined. Despite improvements in imaging and the growing use of renal mass biopsy, diagnosis of malignancy before treatment remains challenging. Management of SRMs has shifted away from radical nephrectomy, with active surveillance and nephron-sparing surgery taking over as the primary modalities of treatment. The optimal treatment strategy for SRMs continues to evolve as factors affecting short-term and long-term outcomes in this patient cohort are elucidated through studies from prospective data registries. Evidence from rapidly evolving research in biomarkers, imaging modalities, and machine learning shows promise in improving understanding of the biology and management of this patient cohort.

Human Breast Cancer Cell Lines Differentially Modulate Signaling from Distant Microenvironments, Which Reflects Their Metastatic Potential.

Metastasis is the stage at which the prognosis substantially decreases for many types of cancer. The ability of tumor cells to metastasize is dependent upon the characteristics of the tumor cells, and the conditioning of distant tissues that support colonization by metastatic cells. In this report, we investigated the systemic alterations in distant tissues caused by multiple human breast cancer cell lines and the impact of these alterations on the tumor cell phenotype. We observed that the niche within the lung, a common metastatic site, was significantly altered by MDA-MB-231, MCF7, and T47 tumors, and that the lung microenvironment stimulated, to differing extents, an epithelial-to-mesenchymal transition (EMT), reducing proliferation, increasing transendothelial migration and senescence, with no significant impact on cell death. We also investigated the ability of an implantable scaffold, which supports the formation of a distant tissue, to serve as a surrogate for the lung to identify systemic alterations. The scaffolds are conditioned by the primary tumor similarly to the lung for each tumor type, evidenced by promoting a pro-EMT profile. Collectively, we demonstrate that metastatic and non-metastatic breast cancers condition distant tissues, with distinct effects on tumor cell responses, and that a surrogate tissue can distinguish the metastatic potential of human breast cancer cell lines in an accessible site that avoids biopsy of a vital organ.

Multiplex electrochemical sensing platforms for the detection of breast cancer biomarkers.

Herein, advancements in electroanalytical devices for the simultaneous detection of diverse breast cancer (BC) markers are demonstrated. This article identifies several important areas of exploration for electrochemical diagnostics and highlights important factors that are pivotal for the successful deployment of novel bioanalytical devices. We have highlighted that the limits of detection (LOD) reported for the multiplex electrochemical biosensor can surpass the sensitivity displayed by current clinical standards such as ELISA, FISH, and PCR. HER-2; a breast cancer marker characterised by increased metastatic potential, more aggressive development, and poor clinical outcomes; can be sensed with a LOD of 0.5 ng/ml using electrochemical multiplex platforms, which falls within the range of that measured by ELISA (from picogram/ml to nanogram/ml). Electrochemical multiplex biosensors are reported with detection limits of 0.53 ng/ml and 0.21 U/ml for MUC-1 and CA 15-3, respectively, or 5.8 × 10-3 U/ml for CA 15-3 alone. The sensitivity of electrochemical assays is improved when compared to conventional analysis of MUC-1 protein which is detected at 11-12 ng/ml, and ≤30 U/ml for CA 15-3 in the current clinical blood tests. The LOD for micro-ribonucleic acid (miRNA) biomarkers analyzed by electrochemical multiplex assays were all notedly superior at 9.79 × 10-16 M, 3.58 × 10-15 M, and 2.54 × 10-16 M for miRNA-155, miRNA-21, and miRNA-16, respectively. The dogma in miRNA testing is the qRT-PCR method, which reports ranges in the ng/ml level for the same miRNAs. Breast cancer exosomes, which are being explored as a new frontier of biosensing, have been detected electrochemically with an LOD of 103-108 particles/mL and can exceed detection limits seen by the tracking and analysis of nanoparticles (∼ 107 particles/ml), flow cytometry, Western blotting and ELISA, etc. A range of concentration at 78-5,000 pg/ml for RANKL and 16-1,000 pg/ml for TNF is reported for ELISA assay while LOD values of 2.6 and 3.0 pg/ml for RANKL and TNF, respectively, are demonstrated by the electrochemical dual immunoassay platform. Finally, EGFR and VEGF markers can be quantified at much lower concentrations (0.01 and 0.005 pg/ml for EGFR and VEGF, respectively) as compared to their ELISA assays (EGRF at 0.31-20 ng/ml and VEGF at 31.3-2,000 pg/ml). In this study we hope to answer several questions: (1) Are the limits of detection (LODs) reported for multiplex electrochemical biosensors of clinical relevance and how do they compare to well-established methods like ELISA, FISH, or PCR? (2) Can a single sensor electrode be used for the detection of multiple markers from one blood drop? (3) What mechanism of electrochemical biosensing is the most promising, and what technological advancements are needed to utilize these devices for multiplex POC detection? (4) Can nanotechnology advance the sensitive and selective diagnostics of multiple BC biomarkers? (5) Are there preferred receptors (antibody, nucleic acid or their combinations) and preferred biosensor designs (complementary methods, sandwich-type protocols, antibody/aptamer concept, label-free protocol)? (6) Why are we still without FDA-approved electrochemical multiplex devices for BC screening?

Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis.

Although pancreatic cancer is a systemic disease that metastasizes early in its course, the signaling systems that promote this behavior remain incompletely understood. In this issue of Cancer Research, Luckett and colleagues identify a paracrine signaling pathway between cancer cells and macrophages that promotes pancreatic cancer metastasis. The authors used immunocompetent murine pancreatic cancer models with high versus low metastatic potential, genetic knockout and complementation strategies, and The Cancer Genome Atlas human data to demonstrate that tumor-secreted mesothelin repolarizes tumor and lung macrophages to a tumor-supportive phenotype. The repolarized macrophages increase secretion of VEGF and S100A9, raising local concentrations. In turn, VEGF enhances colony formation of cancer cells, while S100A9 promotes the recruitment of neutrophils to the lungs and the formation of neutrophil extracellular traps that support tumor metastasis. Together, these findings reveal a systemic signaling pathway that promotes pancreatic cancer metastasis by co-opting macrophages typically protective against cancer to instead promote its spread. See related article by Luckett et al., p. 527.

Neural recordings can differentiate between spontaneously metastasizing melanomas and melanomas with low metastatic potential.

Multiple studies report that melanomas are innervated tumors with sensory and sympathetic fibers where these neural fibers play crucial functional roles in tumor growth and metastasis with branch specificity. Yet there is no study which reports the direct neural recording and its pattern during in-vivo progression of the cancer. We performed daily neural recordings from male and female mice bearing orthotopic metastasizing- melanomas and melanomas with low metastatic poential, derived from B16-F10 and B16-F1 cells, respectively. Further, to explore the origins of neural activity, 6-Hydroxidopamine mediated chemical sympathectomy was performed followed by daily microneurographic recordings. We also performed the daily bioluminescent imaging to track in vivo growth of primary tumors and distant metastasis to the cranial area. Our results show that metastasizing tumors display high levels of neural activity while tumors with low metastatic potential lack it indicating that the presence of neural activity is linked to the metastasizing potential of the tumors. Moreover, the neural activity is not continuous over the tumor progression and has a sex-specific temporal patterns where males have two peaks of high neural activity while females show a single peak. The neural peak activity originated in peripheral sympathetic nerves as sympathectomy completely eliminated the peak activity in both sexes. Peak activities were highly correlated with the distant metastasis in both sexes. These results show that sympathetic neural activity is crucially involved in tumor metastasis and has sex-specific role in malignancy initiation.

Calcitriol promotes M2 polarization of tumor-associated macrophages in 4T1 mouse mammary gland cancer via the induction of proinflammatory cytokines

Our research found that vitamin D3 (VD3) treatment increased lung metastasis in mice with 4T1 murine breast cancer (BC). This study aims to investigate the impact of VD3 on the activation of tumor-associated macrophages (TAMs) in BC. Mice bearing 4T1, E0771, 67NR BC cells, and healthy mice, were fed diets with varying VD3 contents (100—deficient, 1000—normal, and 5000 IU/kg—elevated). Some mice in the 1000 and 100 IU/kg groups received calcitriol. We studied bone metastasis and characterized TAMs and bone marrow-derived macrophages (BMDMs). 4T1 cells had higher bone metastasis potential in the 5000 IU/kg and calcitriol groups. In the same mice, an elevated tumor osteopontin level and M2 polarization of TAMs (MHCIIlow CD44high phenotype) were observed. Gene expression analysis confirmed M2 polarization of 4T1 (but not 67NR) TAMs and BMDMs, particularly in the 100 IU + cal group (increased Mrc1, Il23, and Il6). This polarization was likely due to COX-2/PGE2 induction in 4T1 calcitriol-treated cells, leading to increased proinflammatory cytokines like IL-6 and IL-23. Future studies will explore COX-2/PGE2 as a primary mediator of calcitriol-stimulated inflammation in the BC microenvironment, especially relevant for BC patients with VD3 deficiency and supplementation.

Cancer-associated fibroblast exosomes promote prostate cancer metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment.

Metastasis is the main cause of deaths in prostate cancer (PCa). However, the exact mechanisms underlying PCa metastasis are not fully understood. In this study, we discovered pronounced hypoxia in primary lesions of metastatic PCa(mPCa). The exosomes secreted by cancer-associated fibroblasts (CAFs) under hypoxic conditions significantly enhance PCa metastasis both in vitro and in vivo. Through miRNA sequencing and reverse transcription quantitative PCR (RT-qPCR), we found that hypoxia elevated miR-500a-3p levels in CAFs exosomes. Subsequent RT-qPCR, western blotting, and dual luciferase reporter assays identified F-box and WD repeat domain-containing 7(FBXW7) as a target of miR-500a-3p. In addition, immunohistochemistry revealed that FBXW7 expression decreased with the progression of PCa, while heat shock transcription factor 1(HSF1) expression increased. Introducing an FBXW7 plasmid into PCa cells reduced their metastatic potential and significantly lowered HSF1 expression. These findings suggest that CAFs exosomes drive PCa metastasis via the miR-500a-3p/FBXW7/HSF1 axis in a hypoxic microenvironment. Targeting either hypoxia or exosomal miR-500a-3p could be a promising strategy for PCa management.

Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions.

Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.

Gap junction beta-4 accelerates cell cycle progression and metastasis through MET-AKT activation in pancreatic cancer.

Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta-4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G0/G1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT-2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET-AKT activities. Such data suggest that targeting the GJB4-MET axis could represent a promising new therapeutic strategy for pancreatic cancer.

C9orf10/Ossa regulates the bone metastasis of established lung adenocarcinoma cell subline H322L-BO4 in a mouse model.

Lung cancer frequently metastasizes to the bones. An in vivo model is urgently required to identify potential therapeutic targets for the prevention and treatment of lung cancer with bone metastasis. We established a lung adenocarcinoma cell subline (H322L-BO4) that specifically showed metastasis to the leg bones and adrenal glands. This was achieved by repeated isolation of metastatic cells from the leg bones of mice. The cells were intracardially injected into nude mice. Survival was prolonged for mice that received H322L-BO4 cells versus original cells (H322L). H322L-BO4 cells did not exhibit obvious changes in general in vitro properties associated with the metastatic potential (e.g., cell growth, migration, and invasion) compared with H322L cells. However, the phosphorylation of chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa) was increased in H322L-BO4 cells. This result confirmed the increased anchorage independence through C9orf10/Ossa-mediated activation of Src family tyrosine kinase. Reduction of C9orf10/Ossa by shRNA reduced cells' metastasis to the leg bone and prolonged survival in mice. These findings indicate that H322L-BO4 cells can be used to evaluate the effect of candidate therapeutic targets against bone metastatic lung cancer cells. Moreover, C9orf10/Ossa may be a useful target for treatment of lung cancer with bone metastasis.

Does prostate cancer without cribriform pattern have metastatic potential?

Does prostate cancer without cribriform pattern have metastatic potential?