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1.
Biomater Sci ; 9(9): 3209-3227, 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33949372

RESUMEN

Chitosan (Ch) has recently been used in different studies as a vaccine adjuvant with an ability to modulate the tumor microenvironment (TME). This systematic review aims to elucidate the added value of using Ch-based therapies for immunotherapeutic strategies in cancer treatment, through the exploration of different Ch-based formulations, their capacity to modulate immune cells in vitro and in vivo, and their translational potential for clinical settings. A systematic review was conducted on PubMed, following both inclusion and exclusion steps. Original articles which focused on the immunomodulatory role of Ch-based formulations in the TME were included, as well as its usage as a delivery vehicle for other immunomodulatory molecules. This review illustrates the added value of Ch-based systems to reshape the TME, through the modulation of immune cells using different Ch formulations, namely solutions, films, gels, microneedles and nanoparticles. Generally, Ch-based formulations increase the recruitment and proliferation of cells associated with pro-inflammatory abilities and decrease cells which exert anti-inflammatory activities. These effects correlated with a decreased tumor weight, reduced metastases, reversion of the immunosuppressive TME and increased survival in vivo. Overall, Ch-based formulations present the potential for immunotherapy in cancer. Nevertheless, clinical translation remains challenging, since the majority of the studies use Ch in formulations with other components, implicating that some of the observed effects could result from the combination of the individual effects. More studies on the use of different Ch-based formulations, complementary to standardization and disclosure of the Ch properties used are required to improve the immunomodulatory effects of Ch-based formulations in cancer.


Asunto(s)
Quitosano , Nanopartículas , Neoplasias , Geles , Inmunomodulación , Neoplasias/tratamiento farmacológico , Microambiente Tumoral
2.
Biomater Sci ; 9(9): 3453-3464, 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33949434

RESUMEN

The application of combination immune-chemotherapy makes up for the limitation of monotherapy and achieves superior antitumor activity against cancer. However, combinational therapy is always restricted by poor tumor targeted drug delivery efficacy. Herein, novel T cell membrane cloaking tumor microenvironment-responsive nanoparticles (PBA modified T cell membrane cloaking hyaluronic acid (HA)-disulfide bond-vitamin E succinate/curcumin, shortened as RCM@T) were developed. T cell membrane cloaking not only serves as a protection shell for sufficient drug delivery but also acts as a programmed cell death-1(PD-1) "antibody" to selectively bind the PD-L1 of tumor cells. When RCM@T is intravenously administrated into the blood stream, it accumulates at tumor sites and responds to an acidic pH to achieve a "membrane escape effect" and expose the HA residues of RCM for tumor targeted drug delivery. RCM accumulates in the cytoplasm via CD44 receptor mediated endocytosis and intracellularly releases antitumor drug in the intracellular redox microenvironment for tumor chemotherapy. T cell membrane debris targets the PD-L1of tumor cells for tumor immunotherapy, which not only directly kills tumor cells, but also improves the CD8+ T cell level and facilitates effector cytokine release. Taken together, the as-constructed RCM@T creates a new way for the rational design of a drug delivery system via the combination of stimuli-responsive drug release, chemotherapeutical agent delivery and cell membrane based immune checkpoint blockade immunotherapy.


Asunto(s)
Melanoma , Nanopartículas , Membrana Celular , Humanos , Inmunoterapia , Microambiente Tumoral
3.
Biomater Sci ; 9(9): 3228-3243, 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33949441

RESUMEN

Colorectal cancer (CRC) is one of the deadliest cancers in the world mainly due to metastasis events. Despite improvements, the available treatment modalities for metastatic cases are limited, being generally associated with poor prognosis. As is well known, the immunosuppressive tumor microenvironment (TME) plays a key role in tumorigenesis, promoting cancer cell immune escape and disease progression. In addition, accumulating evidence indicates that the immunosuppressive microenvironment is a critical barrier for antitumor immunity in CRC, being extremely important to modulate the immune microenvironment to inhibit the tumor-promoting immune response. Therefore, new and effective cancer immunotherapeutic approaches demand a better control over the TME to reverse these immunosuppressive conditions. According to the features of different nanomedicines, nanoparticles can constitute a promising strategy, using different materials with the inherent ability to modulate TME and also with the potential to target immunosuppressive cells, to deliver antigens or immunomodulatory agents to eliminate this tumor. In this review, we summarize the importance of the TME in the progression and treatment response of CRC, exploring the potential of the nanotechnology for the development of immunomodulatory therapeutic strategies.


Asunto(s)
Neoplasias Colorrectales , Nanomedicina , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Inmunidad , Inmunoterapia , Microambiente Tumoral
4.
World J Gastroenterol ; 27(15): 1616-1629, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33958847

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death among cancers, it is characterized by poor prognosis and strong chemoresistance. In the PDAC microenvironment, stromal cells release different extracellular components, including CXCL12. The CXCL12 is a chemokine promoting the communication between tumour and stromal cells. Six different splicing isoforms of CXCL12 are known (α, ß, γ, δ, ε, θ) but their role in PDAC has not yet been characterized. AIM: To investigate the specific role of α, ß, and γ CXCL12 isoforms in PDAC onset. METHODS: We used hTERT-HPNE E6/E7/KRasG12D (Human Pancreatic Nestin-Expressing) cell line as a pancreatic pre-tumour model and exposed it to the α, ß, and γ CXCL12 isoforms. The altered expression profiles were assessed by microarray analyses and confirmed by Real-Time polymerase chain reaction. The functional enrichment analyses have been performed by Enrichr tool to highlight Gene Ontology enriched terms. In addition, wound healing assays have been carried out to assess the phenotypic changes, in terms of migration ability, induced by the α, ß, and γ CXCL12 isoforms. RESULTS: Microarray analysis of hTERT-HPNE cells treated with the three different CXCL12 isoforms highlighted that the expression of only a few genes was altered. Moreover, the α and ß isoforms showed an alteration in expression of different genes, whereas γ isoform affected the expression of genes also common with α and ß isoforms. The ß isoform altered the expression of genes mainly involved in cell cycle regulation. In addition, all isoforms affected the expression of genes associated to cell migration, adhesion and cytoskeleton. In vitro cell migration assay confirmed that CXCL12 enhanced the migration ability of hTERT-HPNE cells. Among the CXCL12 splicing isoforms, the γ isoform showed higher induction of migration than α and ß isoforms. CONCLUSION: Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset. However, more investigations are needed to confirm these preliminary observations.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quimiocina CXCL12/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Análisis por Micromatrices , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Isoformas de Proteínas/metabolismo , Microambiente Tumoral
5.
Ann Palliat Med ; 10(4): 4982-4986, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33966433

RESUMEN

Immune checkpoint inhibitors (ICIs) have become an important milestone in the treatment of non-small cell lung cancer (NSCLC). High expression of protein ligand 1 (PD-L1) and tumor mutation burden (TMB) can help to select the dominant population for immunotherapy, but the expression of PD-L1 does not seem to be unchanged. A 61-year-old man with adenocarcinoma of the lung experienced postoperative recurrence. PD-L1 expression was negative before recurrence, and TMB was stable by next-generation sequencing (NGS) test. However, after radiotherapy and chemotherapy, PD-L1 positive expression was found in a re-biopsy specimen, and NGS detection indicated the loss of immune negative predictive genes. The patient achieved a durable response to a posterior-line immunotherapy combined chemotherapy. The tumor microenvironment maybe changed after chemoradiotherapy, which provides an opportunity for patients to benefit from immunotherapy. The use of NGS in dynamic detection and PD-L1 expression may help monitor this change in the tumor microenvironment, the transition from cold to hot tumor. This case maybe provides new clinical evidence that a non-immuno-dominant population in the initial state can be converted to a population with the benefit of immunotherapy after chemoradiotherapy. However, patients who are initially unsuitable for immunotherapy may still need to undergo combined immunotherapy to achieve a clinical benefit.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Antígeno B7-H1/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioradioterapia , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Mutación , Microambiente Tumoral
6.
Adv Exp Med Biol ; 1269: 169-177, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966213

RESUMEN

Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and - in principle - functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and - finally - poor patient outcome.


Asunto(s)
Neoplasias , Fosfatidilinositol 3-Quinasas , Ciclo del Ácido Cítrico , Glucólisis , Humanos , Neoplasias/genética , Microambiente Tumoral
7.
Adv Exp Med Biol ; 1269: 179-183, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966214

RESUMEN

Epithelial-mesenchymal transition (EMT), which is involved in metastasis formation, requires reprogramming of gene expression mediated by key EMT transcription factors. However, signals from the cellular microenvironment, including hypoxia, can also modulate the process of EMT. Hypoxia is often associated with a reduction in the extracellular pH of the tumor microenvironment (acidosis). Whether acidosis alone has an impact on the expression of the EMT markers E-cadherin, N-cadherin, and vimentin was studied in NCI-H358 lung cancer cells. Reducing extracellular pH decreased E-cadherin mRNA, while vimentin and N-cadherin mRNA were doubled. However, at the protein level, E-cadherin and N-cadherin were both reduced, and only vimentin was upregulated. E-cadherin and N-cadherin expression at the cell surface, which is the relevant parameter for cell-cell and cell-matrix interaction, decreased too. The reduction of cell surface proteins was due to diminished protein expression and not changes in cellular localization, since localization of EMT markers in general was not affected by acidosis. Acidosis also affected NCI-H358 cells functionally. Adhesion was decreased when the cells were primed in an acidic medium before measuring cell adherence, which is in line with the reduced expression of cadherins at the cell surface. Additionally, migration was decreased after acidic priming. A possible mechanism for the regulation of EMT markers involves the action of microRNA-203a (miR-203a). In NCI-H358 lung cancer cells, miR-203a expression was repressed by acidosis. Since a decrease in the level of miR-203a has been shown to induce EMT, it might be involved in the modulation of EMT marker expression, adhesion, and migration by the acidic tumor microenvironment in NCI-H358 lung cancer cells.


Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Biomarcadores , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética , Vimentina/genética , Vimentina/metabolismo
8.
Rinsho Ketsueki ; 62(4): 299-304, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33967155

RESUMEN

Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes that suppress the functions of antigen-presenting cells and effector T cells, characterized by the expression of transcription factor forkhead box P3 (FOXP3). Recent studies have reported an increase in the number of Tregs in the bone marrow (BM) of multiple myeloma (MM) patients. However, the role and mechanisms of Treg accumulation in the BM of MM patients remain debatable. Here, we present our data demonstrating the significance of Tregs in the context of MM disease progression. Using the transplantable MM mouse model, we observed a significant increase in Tregs in the BM of MM-injected mice from the early disease stage. We observed extended survival in MM-injected mice with Treg depletion than in mice without Treg depletion, demonstrating direct in vivo evidence that Tregs enhance disease progression in MM. It is noteworthy that type 1 interferon (IFN) signaling is activated in MM-associated Tregs. By using type 1 IFN receptor blocking antibody treatment and type 1 IFN receptor knockout Tregs, we demonstrated a significant decrease in MM-associated Treg proliferation, which was associated with longer survival in MM-injected mice. Thus, we have demonstrated that Tregs play a significant role in MM progression; the function and homeostasis of Tregs are regulated by type 1 IFN secreted in the BM microenvironment.


Asunto(s)
Mieloma Múltiple , Linfocitos T Reguladores , Animales , Factores de Transcripción Forkhead/metabolismo , Homeostasis , Humanos , Ratones , Transducción de Señal , Microambiente Tumoral
9.
Rinsho Ketsueki ; 62(4): 305-313, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33967156

RESUMEN

The bone marrow microenvironment is low in oxygen, promoting a hypoxic response which causes myeloma cells to acquire stem cell properties and enhanced therapy resistance. We performed comprehensive gene and microRNA expression analyses of samples from myeloma patients and cell lines cultured under hypoxia. Through this, we identified the histone demethylase KDM3A, the glycolytic enzyme HK2, and microRNA-210 as factors playing important roles in the behavior of cells under hypoxic conditions. These genes were regulated by the hypoxia-inducible factor HIF. However, we also found that the expression of IRF4 and MYC, factors required for maintenance of differentiation and proliferation was suppressed by hypoxia. This suggests that the regulatory factors that induce drug resistance and the anti-apoptotic capacity of myeloma cells fluctuate with the partial pressure of oxygen in their environment. Based on this premise, a dual treatment strategy in which a dominant clone and a dormant clone adapted to the hypoxic microenvironment are treated simultaneously with orthogonal drugs is a potentially viable strategy to achieve a cure for multiple myeloma.


Asunto(s)
MicroARNs , Mieloma Múltiple , Diferenciación Celular , Hipoxia de la Célula , Glucólisis , Humanos , Hipoxia , Histona Demetilasas con Dominio de Jumonji , MicroARNs/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Microambiente Tumoral
10.
Mater Sci Eng C Mater Biol Appl ; 125: 112100, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33965110

RESUMEN

Complex three-dimensional (3D) cell cultures are being increasingly implemented in biomedical research as they provide important insights into complex cancer biology, and cell-cell and cell-matrix interactions in the tumor microenvironment. However, most methods used today for 3D cell culture are limited by high cost, the need for specialized skills, low throughput and the use of unnatural culture environments. We report the development of a unique biomimetic hydrogel microwell array platform for the generation and stress-free isolation of cancer spheroids. The poly N-isopropylacrylamide-based hydrogel microwell array (PHMA) has thermoresponsive properties allowing for the attachment and growth of cell aggregates/ spheroids at 37 °C, and their easy isolation at room temperature (RT). The reversible phase transition of the microwell arrays at 35 °C was confirmed visually and by differential scanning calorimetry. Swelling/ shrinking studies and EVOS imaging established that the microwell arrays are hydrophilic and swollen at temperatures <35 °C, while they shrink and are hydrophobic at temperatures >35 °C. Spheroid development within the PHMA was optimized for seeding density, incubation time and cell viability. Spheroids of A549, HeLa and MG-63 cancer cell lines, and human lung fibroblast (HLF) cell line generated within the PHMAs had relatively spherical morphology with hypoxic cores. Finally, using MG-63 cell spheroids as representative models, a proof-of-concept drug response study using doxorubicin hydrochloride was conducted. Overall, we demonstrate that the PHMAs are an innovative alternative to currently used 3D cell culture techniques, for the high-throughput generation of cell spheroids for disease modeling and drug screening applications.


Asunto(s)
Hidrogeles , Neoplasias , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular , Humanos , Esferoides Celulares , Microambiente Tumoral
11.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802281

RESUMEN

Many immuno-therapeutic strategies are currently being developed to fight cancer. In this scenario, oncolytic adenoviruses (Onc.Ads) have an interesting role for their peculiar tumor selectivity, safety, and transgene-delivery capability. The major strength of the Onc.Ads is the extraordinary immunogenicity that leads to a strong T-cell response, which, together with the possibility of the delivery of a therapeutic transgene, could be more effective than current strategies. In this review, we travel in the adenovirus (Ads) and Onc.Ads world, focusing on a variety of strategies that can enhance Onc.Ads antitumoral efficacy, passing through tumor microenvironment modulation. Onc.Ads-based therapeutic strategies constitute additional weapons in the fight against cancer and appear to potentiate conventional and immune checkpoint inhibitors (ICIs)-based therapies leading to a promising scenario.


Asunto(s)
Adenoviridae/genética , Neoplasias/terapia , Neoplasias/virología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Animales , Terapia Genética/métodos , Humanos , Linfocitos T/virología , Microambiente Tumoral/genética
12.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807943

RESUMEN

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.


Asunto(s)
Carcinoma Hepatocelular/radioterapia , Compuestos Férricos/farmacología , Neoplasias Hepáticas/radioterapia , Compuestos de Manganeso/farmacología , Nanopartículas/uso terapéutico , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/farmacología , Microambiente Tumoral/efectos de la radiación , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Compuestos Férricos/química , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Compuestos de Manganeso/química , Ratones , Nanopartículas/química , Fármacos Sensibilizantes a Radiaciones/química , Linfocitos T/inmunología , Linfocitos T/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
13.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809660

RESUMEN

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically "cold" tumors into "hot" ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.


Asunto(s)
Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/terapia , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Microambiente Tumoral
14.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803747

RESUMEN

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.


Asunto(s)
Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Transducción de Señal , Neoplasias de la Tiroides/tratamiento farmacológico , Microambiente Tumoral/inmunología
15.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805598

RESUMEN

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/prevención & control , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/prevención & control , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/uso terapéutico , Neoplasias Óseas/genética , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/patología , Comunicación Celular , Citocinas/genética , Citocinas/metabolismo , Humanos , Metástasis Linfática , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/inmunología , Osteoclastos/patología , Transducción de Señal , Escape del Tumor/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/metabolismo
16.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807608

RESUMEN

Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.


Asunto(s)
/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Humanos , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Oncogenes/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
17.
World J Surg Oncol ; 19(1): 123, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865399

RESUMEN

BACKGROUND: Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. METHODS: The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. RESULTS: We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. CONCLUSIONS: In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.


Asunto(s)
Hipoxia/genética , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pancreáticas/patología , Pronóstico
18.
Int J Nanomedicine ; 16: 2597-2613, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833514

RESUMEN

Introduction: Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration. Methods: We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX. Results: SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth. Discussion: Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Nanopartículas/administración & dosificación , Óxido Nítrico/metabolismo , Compuestos Nitrosos/química , Paclitaxel/farmacología , Albúmina Sérica Humana/química , Ondas Ultrasónicas , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Distribución Tisular , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33804861

RESUMEN

Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known about which CREs can provide selective transgene expression in CAFs. We hypothesized that the promoters of FAP, CXCL12, IGFBP2, CTGF, JAG1, SNAI1, and SPARC genes, the expression of whose is increased in CAFs, could be used for transcriptional targeting. Analysis of the transcription of the corresponding genes revealed that unique transcription in model CAFs was characteristic for the CXCL12 and FAP genes. However, none of the promoters in luciferase reporter constructs show selective activity in these fibroblasts. The CTGF, IGFBP2, JAG1, and SPARC promoters can provide higher transgene expression in fibroblasts than in cancer cells, but the nonspecific viral promoters CMV, SV40, and the recently studied universal PCNA promoter have the same features. The patterns of changes in activity of various promoters relative to each other observed for human cell lines were similar to the patterns of activity for the same promoters both in vivo and in vitro in mouse models. Our results reveal restrictions and features for CAF transcriptional targeting.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Regiones Promotoras Genéticas , Transgenes , Microambiente Tumoral/genética , Animales , Línea Celular Tumoral , Quimiocina CXCL12/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Gelatinasas/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína Jagged-1/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Osteonectina/genética , Serina Endopeptidasas/genética , Factores de Transcripción de la Familia Snail/genética , Activación Transcripcional
20.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33804869

RESUMEN

Immunotherapy has emerged as a powerful therapeutic strategy for many malignancies, including lymphoma. As in solid tumors, early clinical trials have revealed that immunotherapy is not equally efficacious across all lymphoma subtypes. For example, immune checkpoint inhibition has a higher overall response rate and leads to more durable outcomes in Hodgkin lymphomas compared to non-Hodgkin lymphomas. These observations, combined with a growing understanding of tumor biology, have implicated the tumor microenvironment as a major determinant of treatment response and prognosis. Interactions between lymphoma cells and their microenvironment facilitate several mechanisms that impair the antitumor immune response, including loss of major histocompatibility complexes, expression of immunosuppressive ligands, secretion of immunosuppressive cytokines, and the recruitment, expansion, and skewing of suppressive cell populations. Accordingly, treatments to overcome these barriers are being rapidly developed and translated into clinical trials. This review will discuss the mechanisms of immune evasion, current avenues for optimizing the antitumor immune response, clinical successes and failures of lymphoma immunotherapy, and outstanding hurdles that remain to be addressed.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Inmunoterapia/métodos , Linfoma/inmunología , Animales , Humanos , Evasión Inmune , Linfoma/terapia , Microambiente Tumoral/inmunología
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