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World Journal of Gastrointestinal... Apr 2024Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it... (Review)
Review
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as , and are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
PubMed: 38660642
DOI: 10.4251/wjgo.v16.i4.1134 -
Histopathology Jun 2024
Topics: Humans; Female; Ovarian Neoplasms; Biomarkers, Tumor; Adenocarcinoma, Mucinous; Thrombospondins; Membrane Proteins; Endopeptidases; Serine Endopeptidases; Neoplasm Invasiveness
PubMed: 38655820
DOI: 10.1111/his.15181 -
Scientific Reports Apr 2024Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that...
Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that impacts interactions with cells in the tumor microenvironment (TME). Thus, there is a pressing need for models to probe the contributions of cellular and noncellular crosstalk. Organoids are promising model systems with the potential to generate a plethora of data including phenotypic, transcriptomic and genomic characterization but still require improvements in culture conditions mimicking the TME. Here, we describe an INTERaction with Organoid-in-MatriX ("InterOMaX") model system, that presents a 3D co-culture-based platform for investigating matrix-dependent cellular crosstalk. We describe its potential to uncover new molecular mechanisms of T cell responses to murine KPC (LSL-Kras/Trp53/p48) PDAC cells as well as PDAC patient-derived organoids (PDOs). For this, a customizable matrix and homogenously sized organoid-in-matrix positioning of cancer cells were designed based on a standardized agarose microwell chip array system and established for co-culture with T cells and inclusion of stromal cells. We describe the detection and orthogonal analysis of murine and human PDAC cell populations with distinct sensitivity to T cell killing that is corroborated in vivo. By enabling both identification and validation of gene candidates for T cell resistance, this platform sets the stage for better mechanistic understanding of cancer cell-intrinsic resistance phenotypes in PDAC.
Topics: Organoids; Animals; Pancreatic Neoplasms; Mice; Carcinoma, Pancreatic Ductal; Humans; T-Lymphocytes; Tumor Microenvironment; Coculture Techniques; Cell Line, Tumor
PubMed: 38654067
DOI: 10.1038/s41598-024-60107-5 -
The Journal of Clinical Investigation Apr 2024CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM)...
CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.
Topics: CD8-Positive T-Lymphocytes; Animals; Tumor Microenvironment; Mice; YAP-Signaling Proteins; Humans; Extracellular Matrix; Sarcoma; Collagen Type VI; Adaptor Proteins, Signal Transducing; Transcription Factors; Oncogenes; Neoplasm Proteins; Collagen Type I
PubMed: 38652549
DOI: 10.1172/JCI167826 -
Clinical and Experimental... 2024Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are... (Review)
Review
Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC's well-established immunologically "cold" tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.
PubMed: 38650920
DOI: 10.2147/CEG.S390655 -
Journal of Nanobiotechnology Apr 2024Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the... (Review)
Review
Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.
Topics: Cancer-Associated Fibroblasts; Exosomes; Tumor Microenvironment; Humans; Animals; Neoplasms; Drug Delivery Systems; Extracellular Matrix; Antineoplastic Agents
PubMed: 38644492
DOI: 10.1186/s12951-024-02452-1 -
Revista Espanola de Medicina Nuclear E... 2024
Topics: Humans; Positron Emission Tomography Computed Tomography; Desmoplastic Small Round Cell Tumor; Radiopharmaceuticals; Gallium Radioisotopes; Male; Gallium Isotopes; Female; Middle Aged
PubMed: 38643836
DOI: 10.1016/j.remnie.2024.500013 -
BMC Musculoskeletal Disorders Apr 2024Desmoplastic fibroma is an extremely rare primary bone tumor. Its characteristic features include bone destruction accompanied by the formation of soft tissue masses....
BACKGROUND
Desmoplastic fibroma is an extremely rare primary bone tumor. Its characteristic features include bone destruction accompanied by the formation of soft tissue masses. This condition predominantly affects individuals under the age of 30. Since its histology is similar to desmoid-type fibromatosis, an accurate diagnosis before operation is difficult. Desmoplastic fibroma is resistant to chemotherapy, and the efficacy of radiotherapy is uncertain. Surgical excision is preferred for treatment, but it entails high recurrence. Further, skeletal reconstruction post-surgery is challenging, especially in pediatric cases.
CASE PRESENTATION
Nine years ago, a 14-year-old male patient presented with a 4-year history of progressive pain in his left wrist. Initially diagnosed as fibrous dysplasia by needle biopsy, the patient underwent tumor resection followed by free vascularized fibular proximal epiphyseal transfer for wrist reconstruction. However, a histological examination confirmed a diagnosis of desmoplastic fibroma. The patient achieved bone union and experienced a recurrence in the ipsilateral ulna 5 years later, accompanied by a wrist deformity. He underwent a second tumor resection and wrist arthrodesis in a single stage. The most recent annual follow-up was in September 2023; the patient had no recurrence and was satisfied with the surgery.
CONCLUSIONS
Desmoplastic fibroma is difficult to diagnose and treat, and reconstruction surgery after tumor resection is challenging. Close follow-up by experienced surgeons may be beneficial for prognosis.
Topics: Adolescent; Humans; Male; Bone Neoplasms; Fibroma; Fibroma, Desmoplastic; Fibula; Follow-Up Studies; Tomography, X-Ray Computed
PubMed: 38643068
DOI: 10.1186/s12891-024-07454-6 -
Frontiers in Veterinary Science 2024Ameloblastoma in dogs most often has a highly conserved acanthomatous cell morphology and is recognized as canine acanthomatous ameloblastoma (CAA) while conventional...
Ameloblastoma in dogs most often has a highly conserved acanthomatous cell morphology and is recognized as canine acanthomatous ameloblastoma (CAA) while conventional ameloblastoma (CA) makes up a smaller yet morphologically diverse group of epithelial odontogenic tumors. In humans, a rare desmoplastic histological subtype has distinctive clinical, radiological, and microscopic features. Desmoplastic ameloblastoma (DA) has not previously been described in dogs, although it has been rarely referenced in the veterinary literature. This is the first thorough description of a case series of DA in dogs and describes clinical presentation, diagnostic imaging findings, histopathological features for diagnosis, and treatment outcome. Clinically, DA most often presents as a mass or swelling in the rostral mandible or maxilla of middle age to older dogs. On diagnostic imaging, the lesion has a radiolucent or mixed pattern with well-defined borders and variable loculation. As a solid, fibrous tumor with obscured odontogenic epithelium, DA is challenging to diagnose histologically and can mimic several other oral tumors, both benign and malignant. As an ameloblastoma, the biological behavior of DA is locally destructive yet benign and prognosis is favorable following surgical excision.
PubMed: 38638641
DOI: 10.3389/fvets.2024.1362237 -
Journal of Advanced Research Apr 2024Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a...
Co-delivery of fucoxanthin and Twist siRNA using hydroxyethyl starch-cholesterol self-assembled polymer nanoparticles for triple-negative breast cancer synergistic therapy.
INTRODUCTION
Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance.
OBJECTIVES
Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop.
METHODS AND RESULTS
Herein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis.
CONCLUSION
Systematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.
PubMed: 38636588
DOI: 10.1016/j.jare.2024.04.017