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PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗

PubMed1996

Human protection against non-genotoxic carcinogens in the US without the Delaney Clause.

Cancers of many types are major chronic diseases with a high fatality rate and a high cost to society. In the USA, the Delaney Clause was implemented in 1958 because the public believed that many cancers stem from food additives and food contaminants. In the intervening years, research has provided key information about the mechanisms of carcinogenesis and demonstrated that there are two major classes of carcinogens, genotoxic and non-genotoxic. Two case reports are presented, of sodium saccharin and ethylenebisdithiocarbamates that were banned based on the Delaney Clause in an unjustified manner, based on the underlying mechanisms not relevant for non-genotoxic carcinogens. Also, the causes of major cancers have been discovered. Most cancers are associated with lifestyle, specifically tobacco and excessive alcohol use, inappropriate nutritional traditions, and lack of exercise. These lifestyle components involve now known genotoxic carcinogens and importantly, non-genotoxic carcinogens. The effect of non-genotoxic carcinogens is highly dose dependent and also reversible upon lowering the dose below a threshold. Thus, it is quite possible to lower human cancer risk, and also the risk of related chronic diseases such as coronary heart disease, hypertension and stroke, adult on-set diabetes, by proper lifestyle adjustments. Clearly, the Delaney Clause plays no role in disease prevention.

Carcinogenicity Tests↗

PubMed2007

The commonality of plasticity underlying multipotent tumor cells and embryonic stem cells.

Aggressive cancer cells and pluripotent stem cells converge in their capacity for self-renewal, proliferation and plasticity. Recent studies have capitalized on these similarities by demonstrating that tumors arise from specific cancer stem cell populations that, in a manner reminiscent of normal stem cells, are able to both self-renew and give rise to a heterogeneous tumor population. This stem cell like function of aggressive cancer cells is likely attributable to the ectopic expression of embryonic factors such as Nodal and Cancer Testis Specific Antigens (CTAs), which maintain a functional plasticity by promoting pluripotency and immortality. During development, the expression of these embryonic factors is tightly regulated by a dynamic array of mediators, including the spatial and temporal expression of inhibitors such as Lefty, and the epigenetic modulation of the genome. In aggressive cancer cells, particularly melanoma, this balance of regulatory mediators is disrupted, leading to the aberrant expression of pluripotency-associated genes. By exposing aggressive cancer cells to embryonic microenvironments, this balance of regulatory mediators is restored, thereby reprogramming tumor cells to a more benign phenotype. These stem cell-derived mediators, as well as the genes they regulate, provide therapeutic targets designed to specifically differentiate and eradicate aggressive cancers.

Cell Lineage↗

PubMed2026

Paired analysis of primary adenoid cystic carcinoma and derived cell lines reveals a mesenchymal and stem-like shift associated with therapy resistance.

Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by slow but persistent growth, frequent local recurrence, and late metastatic progression. Patients with unresectable, recurrent, or metastatic disease have limited therapeutic options. Efforts to identify effective therapeutic targets have been hindered by the limited availability of well-characterized ACC models. In this study, we established 11 ACC cell lines and performed RNA sequencing of nine cell lines and their matched primary tumors to evaluate the preservation and evolution of molecular and lineage-associated characteristics during cell line establishment. Comparative transcriptomic analysis revealed reduced epithelial and luminal differentiation programs in the cell lines, accompanied by enrichment of myoepithelial, EMT-, and cancer stem cell-associated transcriptional programs. Digital deconvolution and single-sample gene set enrichment analysis supported enrichment of hybrid EMT/stem-like states during in vitro propagation, while comparison with publicly available primary-recurrent ACC data demonstrated partial preservation of recurrence-associated plasticity and invasion programs. Protein-level validation of representative epithelial, myoepithelial, EMT, and stemness markers supported the major transcriptomic changes. In addition, a cell line with a higher stemness signature showed reduced sensitivity to cisplatin. Together, these findings indicate that ACC cell line establishment is associated with transcriptional reprogramming and enrichment of plastic, EMT/stem-like states while retaining selected ACC lineage characteristics. These models provide experimentally tractable platforms for investigating ACC progression, therapeutic response, and mechanisms of treatment resistance.

Adenoid cystic carcinoma↗

PubMed2003

Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors.

We have used the hematopoietic system as a model to investigate whether acute myeloid leukemia arises exclusively from self-renewing stem cells or also from short-lived myeloid progenitors. When transduced with a leukemogenic MLL fusion gene, prospectively isolated stem cells and myeloid progenitor populations with granulocyte/macrophage differentiation potential are efficiently immortalized in vitro and result in the rapid onset of acute myeloid leukemia with similar latencies following transplantation in vivo. Regardless of initiating cell, leukemias displayed immunophenotypes and gene expression profiles characteristic of maturation arrest at an identical late stage of myelomonocytic differentiation, putatively a monopotent monocytic progenitor stage. Our findings unequivocally establish the ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene, and support the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin.

Acute Disease↗

PubMed2025

Single-cell glycome and transcriptome profiling enabled by a library of anti-glycan antibodies.

Glycans play critical roles in cellular processes and clinical applications, but they remain difficult to study due to a shortage of well-characterized anti-glycan reagents and high-throughput technologies for glycome profiling, especially ones capable of single-cell resolution. To meet these needs, we generated a database of 650 anti-glycan antibody sequences, recombinantly expressed a library of 154 antibodies, and extensively characterized their binding properties using glycan microarrays. In addition to providing valuable information and resources for the field, the sequence database and microarray data also enabled development of "Glycomic-seq" (Glycome profiling via multiplexed immunoglobulins combined with sequencing), a DNA-barcoded anti-glycan antibody platform that enables high-throughput, single-cell profiling of both RNA and cell-surface glycan expression. Using Glycomic-seq, we profiled two isogenic colorectal cancer cell lines. The results revealed various glycans associated with cancer stem cells and metastasis, demonstrating the power of integrating glycomic information with multi-omic efforts to discover biomarkers and therapeutic targets.

Polysaccharides↗

PubMed2004

Regulation of hematopoietic stem cell growth.

Hematopoietic stem cells (HSC) must balance self-renewal and differentiation to provide sufficient primitive cells to sustain hematopoiesis, while generating more mature cells with specialized capabilities. The enhanced self-renewal capacity of primitive HSCs enables their ability to sustain hematopoiesis throughout decades of life and their ability to repopulate a host when used therapeutically in bone marrow transplantation. However, hematopoietic cell perturbations resulting in unchecked self-renewal participate in leukemogenesis. While mechanisms governing self-renewal are still being uncovered, they are thought to bear relationship to the malignant process in a variety of tumor types and may therefore provide useful therapeutic targets in putative cancer stem cells. This review discusses molecular mechanisms recently defined to participate in HSC governance and highlights features of stem cell interactions with the microenvironment that may help guide therapies directed at HSCs.

Animals↗

PubMed2005

Long-term self-renewal of postnatal muscle-derived stem cells.

The ability to undergo self-renewal is a defining characteristic of stem cells. Self-replenishing activity sustains tissue homeostasis and regeneration. In addition, stem cell therapy strategies require a heightened understanding of the basis of the self-renewal process to enable researchers and clinicians to obtain sufficient numbers of undifferentiated stem cells for cell and gene therapy. Here, we used postnatal muscle-derived stem cells to test the basic biological assumption of unlimited stem cell replication. Muscle-derived stem cells (MDSCs) expanded for 300 population doublings (PDs) showed no indication of replicative senescence. MDSCs preserved their phenotype (ScaI+/CD34+/desmin(low)) for 200 PDs and were capable of serial transplantation into the skeletal muscle of mdx mice, which model Duchenne muscular dystrophy. MDSCs expanded to this level exhibited high skeletal muscle regeneration comparable with that exhibited by minimally expanded cells. Expansion beyond 200 PDs resulted in lower muscle regeneration, loss of CD34 expression, loss of myogenic activity, and increased growth on soft agar, suggestive of inevitable cell aging attributable to expansion and possible transformation of the MDSCs. Although these results raise questions as to whether cellular transformations derive from cell culturing or provide evidence of cancer stem cells, they establish the remarkable long-term self-renewal and regeneration capacity of postnatal MDSCs.

Aging↗

PubMed2026

CTGF/CCN2 Promotes Invasive Growth in Cervical Cancer Spheroids and Is Associated With Metastatic Cervical Cancer Tissue.

BACKGROUND/AIM: Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS: CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS: Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) ≥ 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION: In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.

Humans↗

PubMed2006

Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth.

Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G(1) phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic-severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution.

Adult↗

PubMed2026

Drug resistance in breast cancer brain metastasis: mechanisms and therapeutic strategies.

Brain-metastatic breast cancer (BMBC) is a severe complication of advanced breast cancer, affecting 15-30% of metastatic patients, particularly those with HER2-positive or triple-negative subtypes, and is associated with dismal prognosis and median survival under 12 months. Therapeutic resistance, driven by the central nervous system's sanctuary role, poses a major barrier to effective treatment, often resulting in discordant intracranial versus extracranial responses. This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses. Key drivers include genetic/epigenetic alterations, BBB-mediated drug exclusion via efflux transporters, and microenvironmental interactions with astrocytes and immune cells that promote survival signaling. Additional factors encompass cancer stem cell plasticity/dormancy enabling therapy evasion, metabolic reprogramming and extracellular matrix remodeling that shields tumor from drugs. We highlight how these interconnected pathways create a protective niche for metastatic cells. Promising strategies to overcome resistance include BBB-penetrant agents, antibody-drug conjugates, nanomedicine, and combination therapies targeting the tumor microenvironment and epigenetics. By integrating mechanistic insights with translational opportunities, this review emphasizes the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.

Humans↗

PubMed2004

Microarray and serial analysis of gene expression analyses identify known and novel transcripts overexpressed in hematopoietic stem cells.

The human CD34(+)/CD38(-)/Lin(-) cell subset, comprising approximately 1-10% of the CD34(+) cell population, contains few of the less primitive hematopoietic (lineage-committed) progenitor cells (HPCs) but most of the primitive in vivo engrafting (lympho-)hematopoietic stem cells (HSCs). We analyzed gene expression in CD34(+)/CD38(-)/Lin(-) cell populations isolated from normal human adult donor bone marrow, neonatal placental/umbilical cord blood, and mobilized adult donor peripheral blood stem-progenitor cells. As measured by Affymetrix microarrays, 4746 genes were expressed in CD34(+)/CD38(-)/Lin(-) cells from all three tissues. We also determined the transcriptomes of the stem cell-depleted, HPC-enriched CD34(+)/[CD38/Lin](++) cell population from each tissue. Comparison of CD34(+)/CD38(-)/Lin(-) (HSC-enriched) versus CD34(+)/[CD38/Lin](++) (HPC-enriched, HSC-depleted) cells from each tissue yielded 81 genes overrepresented and 90 genes underrepresented, common to all three of the CD34(+)/CD38(-)/Lin(-) cell populations. These transcripts, which are selectively expressed in HSCs from all three tissues, include a number of known genes (e.g., transcription factors, receptors, and signaling molecules) that might play roles in key functions (e.g., survival, self-renewal, differentiation, and/or migration/adhesion) of human HSCs. Many genes/transcripts of unknown function were also detected by microarray analysis. Serial analysis of gene expression of the bone marrow HSC and HPC populations confirmed expression of most of the overrepresented transcripts for which reliable serial analysis of gene expression tags were detected and additionally suggested that current microarrays do not detect as many as 30% of the transcripts expressed in HSCs, including a number of previously unknown transcripts. This work is a step toward full definition of the transcriptome of normal human HSCs and may identify new genes involved in leukemogenesis and cancer stem cells.

ADP-ribosyl Cyclase↗

PubMed1996

Immunotherapy I: Cyclosine gene transfer strategies.

The cytokine approach to gene therapy of cancer stems from early studies of direct, repeated injection of recombinant cytokines at the tumor site, and extension of the bystander effect that enables a few cytokine gene transduced cells in a tumor to bring about its total destruction. This effect can be extended through the immune system, since cytokine-activated regression of a small mass of tumor cells can afford systemic protection. Transduced cells used as a vaccine provide a local concentration of both cytokine and tumor antigens. Cytokines sustain antigen uptake and presentation by increasing the immunogenic potential of the environment through the recruitment of antigen presenting cells and leukocytes, and activation of a cascade of events which amplify and tone up the efficacy of a vaccine. The promises and difficulties of this approach are discussed by considering what is still missing from experimental studies and what can best be done as soon as possible in animals and humans to reach compelling conclusions.

Animals↗

PubMed2006

Colorectal carcinoma: from tumorigenesis to treatment.

Colorectal carcinoma (CRC) is a complicated and often fatal genetic disease. Fortunately, owing to rapid expansion of knowledge and technology development in oncology, much progress has been made regarding the diagnosis, understanding of the molecular genetics and malignant progression, as well as the novel regimens of CRC. In this review, we summarize the staging system, the most critical genetic and epigenetic alterations, the pleiotropic effects of MMP-7, the controversial roles of Hedgehog signaling, the intriguing involvement of thymosin beta-4, and the possible contribution of the putative colon (cancer) stem cells in CRC tumorigenesis. Current treatments as well as several potentially applicable therapeutic strategies for CRC are also discussed.

Animals↗

PubMed2005

Fluoxetine and reversal of multidrug resistance.

This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic.

Animals↗

PubMed2026

Pharmacologic inhibition of SOX9-CDK4 by CYD-4-61 impairs gastric adenocarcinoma growth and amplifies anti-PD-1 response.

Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.

Animals↗

PubMed2006

Adjuvant treatment strategies for pancreatic cancer.

Pancreatic cancer is a difficult and unsolved surgical problem. It remains one of the top five causes of cancer-related deaths and has the lowest 5-year survival of any cancer, largely due to late diagnosis, low resection rates, and local recurrence. Clinical trials examining the optimal timing and delivery of adjuvant therapies for pancreatic cancer have yielded controversial results. Although most experts agree that the addition of chemotherapy has survival benefit in patients with resectable pancreatic cancer, there is no consensus regarding the optimal therapeutic agents, timing (neoadjuvant versus adjuvant), and the addition of radiation therapy to the treatment regimen. Multiple phase III trials are in progress in efforts to examine these issues. Additionally, exciting progress has been made with novel chemotherapeutic combinations, and alternative treatment modalities including interferon-alpha, immunotherapy, and pancreatic cancer stem cells. Given the high failure pattern after surgical resection, with more than half of patients developing locoregional recurrence, all patients undergoing pancreaticoduodenectomy are candidates for adjuvant therapy.

Adenocarcinoma↗

PubMed2025

Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas.

INTRODUCTION: Lung neuroendocrine carcinomas (Lu-NECs) are rare, highly aggressive lung tumors with poor prognosis and limited therapeutic options. Understanding the tumor immune microenvironment (TIME) is crucial towards personalized therapeutic strategies. OBJECTIVES: This study aims to systematically characterize the heterogeneity and complexity of the TIME in Lu-NECs by integrating proteomic, transcriptomic, and genomic data. METHODS: We performed comprehensive immune-proteomic profiling of 76 Lu-NECs across diverse histopathological subtypes to elucidate intra-tumoral TIME heterogeneity at the proteomic level. Validation was conducted in multiple independent cohorts, including 112 Lu-NECs using immunohistochemistry, 147 Lu-NECs, and 17 small cell lung carcinoma samples using transcriptomics. We integrated proteomic, transcriptomic, genomic, and clinical data to assess molecular, immunological, and clinical features, as well as therapeutic vulnerabilities across different immune subtypes. RESULTS: We delineated the immuno-proteomic landscape of Lu-NECs and identified two major immuno-proteomic clusters with distinct immunological, molecular, and clinical characteristics. IPC1 was characterized by high immune cell infiltration, while IPC2 exhibited sparse immune cell presence. Genomic analysis revealed distinct mutational patterns, with IPC1 showing a higher incidence of APOBEC-associated mutation signatures and IPC2 being enriched for mutations associated with defective DNA mismatch repair and tobacco-related mutagens. Functional analyses indicated that IPC1 was related to immune and oncogenic signaling activity, whereas IPC2 was associated with cancer stemness and proliferation-related features. Furthermore, IPC1 and IPC2 demonstrated histological subtype-specific clinical benefits from postoperative chemotherapy. Finally, we developed a machine learning model (iPROM) to predict Lu-NECs immune classification and improve risk stratification, which was validated across multiple independent cohorts. CONCLUSIONS: This study advances the understanding of the tumor immune microenvironment in Lu-NECs through multi-omics characterization and highlights potential personalized therapeutic vulnerabilities tailored to the specific immune landscapes of Lu-NECs.

Humans↗