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Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4+CD25+FOXP3+ T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4+CD25+FOXP3+ Treg cells from infiltrating CD4+ T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFNγ production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4+CD25+FOXP3+ Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGFß, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4+CD25+FOXP3+ Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGFß, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.
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Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.
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Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Macrófagos , Neovascularização Patológica , RecidivaRESUMO
Post-translational modification (PTM) is important in controlling many biological processes by changing the structure and function of a protein. Protein methylation is an important PTM, and the role of methyltransferases has been implicated in numerous cellular functions. Protein L-isoaspartyl methyltransferase (PIMT) is ubiquitously expressed in almost all organisms and govern important cellular processes including apoptosis. Among other functions, PIMT has also been identified as a potent oncogene because it destabilizes the structure of the tumor suppressor p53 via methylation at the transactivation domain. In the present study we identified that out of the three methyltransferase inhibitors tested, namely, S-adenosyl-l-homocysteine (AdoHcy), adenosine and adenosine dialdehyde (AdOx), only AdOx augments p53 expression by destabilizing PIMT structure, as evident from far-UV CD. The effect of the inhibitors, AdOx in particular, to the structure of PIMT, and the binding of PIMT to the p53 transactivation domain have been investigated by docking and molecular dynamics simulations. AdOx significantly increases p53 accumulation and nuclear translocation in colon cancer cells, triggering the p53-mediated apoptotic pathway. To better understand the molecular mechanisms underlying p53 accumulation in colon cancer cells, we observed that the level of PIMT is considerably lower in AdOx-treated cells, reducing its association with p53, which stabilized p53. p53 then transactivated BAX, increasing the BAX: BCL-2 ratio and causing colon cancer cell death.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adenosina/farmacologia , Apoptose , Metiltransferases/metabolismoRESUMO
B cells are an essential component of humoral immunity. Their primary function is to mount antigen-specific antibody responses to eliminate pathogens. Despite an increase in B-cell number, we found that serum-IgG levels were low in patients with breast cancer. To solve this conundrum, we used high-dimensional flow cytometry to analyze the heterogeneity of B-cell populations and identified a tumor-specific CD19+CD24hiCD38hi IL10-producing B regulatory (Breg)-cell subset. Although IL10 is a Breg-cell marker, being an intracellular protein, it is of limited value for Breg-cell isolation. Highly expressed Breg-cell surface proteins CD24 and CD38 also impede the isolation of viable Breg cells. These are hurdles that limit understanding of Breg-cell functions. Our transcriptomic analysis identified, CD39-negativity as an exclusive, sorting-friendly surface marker for tumor-associated Breg cells. We found that the identified CD19+CD39âIL10+ B-cell population was suppressive in nature as it limited T helper-cell proliferation, type-1 cytokine production, and T effector-cell survival, and augmented CD4+FOXP3+ regulatory T-cell generation. These tumor-associated Breg cells were also found to restrict autologous T follicular helper-cell expansion and IL21 secretion, thereby inhibiting germinal transcript formation and activation-induced cytidine deaminase expression involved in H-chain class-switch recombination (CSR). This isotype-switching abnormality was shown to hinder B-cell differentiation into class-switched memory B cells and subsequent high-affinity antibody-producing plasma B cells, which collectively led to the dampening of IgG-mediated antibody responses in patients with cancer. As low IgG is associated with poor prognosis in patients with cancer, Breg-cell depletion could be a promising future therapy for boosting plasma B cell-mediated antibody responses.
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Interleucina-10 , Neoplasias , Humanos , Formação de Anticorpos , Antígenos CD19 , Linfócitos T CD4-Positivos , Imunoglobulina GRESUMO
Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.
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Neoplasias da Mama , Linfócitos T Reguladores , Animais , Neoplasias da Mama/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Histona Acetiltransferases , Humanos , Camundongos , Receptores CCR4/metabolismo , Microambiente TumoralRESUMO
The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.
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The components of the immune system play a very sincere and crucial role in combating tumors. However, despite their firm efforts of elimination, tumor cells cleverly escape the surveillance process by adopting several immune evasion mechanisms. The conversion of immunogenicity of tumor microenvironment into tolerogenic is considered as a prime reason for tumor immune escape. Therapeutically, different immunotherapies have been adopted to block such immune escaping routes along with better clinical outcomes. Still, the therapies are haunted by several drawbacks. Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor's way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes.
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Plasticity between Th17 and Treg cells is regarded as a crucial determinant of tumor-associated immunosuppression. Classically Th17 cells mediate inflammatory responses through production of cytokine IL17. Recently, Th17 cells have also been shown to acquire suppressive phenotypes in tumor microenvironment. However, the mechanism by which they acquire such immunosuppressive properties is still elusive. Here, we report that in tumor microenvironment Th17 cell acquires immunosuppressive properties by expressing Treg lineage-specific transcription factor FOXP3 and ectonucleotidase CD73. We designate this cell as Th17reg cell and perceive that such immunosuppressive property is dependent on CD73. It was observed that in classical Th17 cell, GFI1 recruits HDAC1 to change the euchromatin into tightly-packed heterochromatin at the proximal-promoter region of CD73 to repress its expression. Whereas in Th17reg cells GFI1 cannot get access to CD73-promoter due to heterochromatin state at its binding site and, thus, cannot recruit HDAC1, failing to suppress the expression of CD73.
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Proteínas de Ligação a DNA/metabolismo , Histona Desacetilase 1/metabolismo , Imunomodulação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Transcrição/metabolismo , 5'-Nucleotidase/metabolismo , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras Genéticas , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The initiation of new blood vessel formation (neo-angiogenesis) is one of the primary requirements for the establishment of tumor. As the tumor grows beyond a certain size, a hypoxic-condition arises in the inner core of tumor, triggering the release of chemokines, which attract T-regulatory (Treg) cells in the tumor-site. The presence of FOXP3, a lineage-specific transcription factor, expressing Treg cells in various types of tumor implements immunosuppressive and tumor-promoting strategies. One such strategy is the invitation of endothelial cells for neo-vascularization in the tumor site. Here we report that as the disease progresses, Treg cells from breast cancer patients are capable of secreting high-amount of VEGFA. The VEGFA promoter lacks Treg-specific transcription factor FOXP3 binding site. FOXP3 in association with locus-specific transcription factor STAT3 binds to VEGFA promoter to induce its transcription in Treg cells obtained from breast cancer patients. Treg cell-secreted VEGFA induces neo-angiogenesis from endothelial cells under in-vitro conditions. Targeting Tregs in mice with breast tumor reduces tumor growth as well as the level of neo-angiogenesis in the tumor tissue.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/patologia , Linfócitos T Reguladores/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Prognóstico , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/metabolismo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.
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A large number of cancer patients relapse after chemotherapeutic treatment. The immune system is capable of identifying and destroying cancer cells, so recent studies have highlighted the growing importance of using combinatorial chemotherapy and immunotherapy. However, many patients have innate or acquired resistance to immunotherapies. Long-term follow-up in a pooled meta-analysis exhibited long-term survival in approximately 20% of patients treated with immune checkpoint inhibitors or the adoptive transfer of chimeric T cells. It has been reported that high levels of immunoregulatory cells in cancer patients contribute to immunotherapy resistance via immunosuppression. Among the most important regulatory cell subtypes are the CD4+ T-regulatory cells (Tregs), identified by their expression of the well-characterized, lineage-specific transcription factor FOXP3. In addition to CD4+ Tregs, other regulatory cells present in the tumor microenvironment, namely CD8+ Tregs and IL10-producing B-regulatory cells (Bregs) that also modulate the immune response in solid and lymphoid tumors. These cells together have detrimental effects on tumor immune surveillance and anti-tumor immunity. Therefore, targeting these regulatory lymphocytes will be crucial in improving treatment outcomes for immunotherapy.
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Linfócitos T Reguladores , Imunoterapia , Neoplasias , Terapia de ImunossupressãoRESUMO
Anoikis resistance is an essential property of cancer cells that allow the extra-cellular matrix-detached cells to survive in a suspended state in body fluid in order to metastasize and invade to distant organs. It is known that integrins play an important role in anoikis resistance, but detailed mechanisms are not well understood. Here we report that highly metastatic colon cancer cells showed a higher degree of anoikis resistance than the normal intestinal epithelial cells. These anoikis-resistant cancer cells express high-levels of integrin-α2, ß1, and activated EGFR in the anchorage-independent state than the anchorage-dependent state. In contrast, normal intestinal epithelial cells failed to elevate these proteins. Interestingly, a higher co-association of EGFR with integrin-α2ß1/-α5ß1 was observed on the surface of anoikis-resistant cells. Thus, in the absence of extra-cellular matrix, integrins in association with EGFR activates downstream effectors ERK and AKT and suppress Caspase-3 activation to induce anoikis resistance as was confirmed from the gene-ablation and pharmacological inhibitor studies. Interestingly, these anoikis-resistant cancer cells express high-level of cancer stem cell signatures (CD24, CD44, CD133, EpCAM) and pluripotent stem cell markers (OCT-4, SOX-2, Nanog) as well as drug-resistant pumps (ABCG2, MDR1, MRP1). Altogether, our findings unravel the interplay between integrin-α2ß1/-α5ß1 and EGFR in anoikis resistance and suggest that the resistant cells are cancer initiating or cancer stem cells, which may serve as a promising target to combat metastasis of cancer.
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Anoikis , Neoplasias do Colo/metabolismo , Integrina alfa2beta1/metabolismo , Células-Tronco Neoplásicas/metabolismo , Antígeno AC133/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anoikis/genética , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Integrina alfa2beta1/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteína Homeobox Nanog/metabolismo , Proteínas de Neoplasias/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismoRESUMO
BACKGROUND: Recently various types of immunotherapies have made immense progress in combating cancer. Adoptive cell therapy, being one of the most favorable forms of immunotherapy, is rapidly moving from bench to bed. MAIN BODY: Different types of T-memory cells are being used as promising candidates for adoptive cell therapy: T effector memory (TEM) cells which are terminally differentiated memory cells and attain effector function soon after re-stimulation; T central memory (TCM) cells which differentiate into effector T-memory subsets and T-effector cells after antigenic stimulation; and tissue T resident memory (TRM) cells which fight the tumor insult at the peripheral tissues. Recently, a new subtype of T-memory cells, T stem cell memory (TSCM) have been identified as the most favorable candidate for adoptive cell therapy as they exhibit higher persistence, anti-tumor immunity and self-renewal capacity in the tumor-bearing host. CONCLUSION: In this review, we briefly describe the concept and types of T-memory cells as well as their role as potential candidates for anti-cancer immunotherapy.
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Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Autorrenovação Celular , Citotoxicidade Imunológica , Humanos , Memória Imunológica , Neoplasias/imunologia , Células-TroncoRESUMO
The nuclease hypersensitive element III1 (NHE III1) upstream c-MYC promoter harbors a transcription-silencing G-quadruplex (Pu27) element. Dynamic turnover of various transcription factors (TFs) across Pu27 to control c-MYC transcription homeostasis is enigmatic. Here, we reveal that native Pu27 evolves truncated G-quadruplex isomers (Pu19, Pu22, Pu24, and Pu25) in cells that are optimal intracellular targets of specific TFs in a sequence- and structure-dependent manner. Nuclear magnetic resonance and isothermal titration calorimetry envisaged that NM23-H2 (nucleoside diphosphate kinase) and nucleolin induce conformational fluctuations in Pu27 to sample specific conformationally restricted conformer(s). Structural investigations revealed that the flanking guanines at 5'-Pu27 control solvent exposure at G-quartets upon NM23-H2 and nucleolin binding driving Pu27 unfolding and folding, respectively. Transient chromatin immunoprecipitations confirmed that NM23-H2 drives the conformation switch to Pu24 that outcompetes nucleolin recruitment. Similarly, nucleolin arrests Pu27 in the Pu22 conformer minimizing NM23-H2 binding at Pu27. hnRNPK (heterogeneous nuclear ribonucleoprotein K) positively regulates NM23-H2 and nucleolin association at Pu27 despite their antagonism. On the basis of these results, we simulated the transcription kinetics in a feed-forward loop in which the transcription output responds to hnRNPK-induced early activation via NM23-H2 association, which favors Pu24 formation at NHE III1 reducing nucleolin occupancy and driving quadruplex unfolding to initiate transcription. NM23-H2 further promotes hnRNPK deposition across NHE III1 altering Pu27 plasticity that finally enriches the nucleolin abundance to drive Pu22 formation and weaken NM23-H2 binding to extinguish transcription. This mechanism involves three positive feedback loops (NM23-H2-hnRNPK, NM23-H2-CNBP, and hnRNPK-nucleolin) and one negative feedback loop (NM23-H2-nucleolin) controlling optimal turnover and residence time of TFs at Pu27 to homeostatically regulate c-MYC transcription.
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DNA/química , Quadruplex G , Homeostase , Proteínas Proto-Oncogênicas c-myc/química , Fatores de Transcrição/química , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Humanos , Isomerismo , Nucleosídeo NM23 Difosfato Quinases/química , Nucleosídeo NM23 Difosfato Quinases/genética , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , NucleolinaRESUMO
Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.
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Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Trifosfato de Adenosina/química , Trifosfato de Adenosina/genética , Andrographis paniculata , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno/farmacologia , Diterpenos/química , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Laminina/farmacologia , Neoplasias/genética , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Extratos Vegetais/química , Conformação Proteica/efeitos dos fármacos , Proteoglicanas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
CD8+ T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3+ CD8+ Treg cells, similar to CD4+ Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGFß. At an early stage of tumor development, we have identified a subset of FOXP3- CD8+ CD25+ KIR+ CD127- Treg-like cells, which are IFNγ+ . However, this early-induced CD8+ CD25+ CD127- T-cell subset is certainly distinct from the IFNγ+ CD8+ T-effector cells. These CD8+ CD25+ CD127- T cells express other FOXP3- CD8+ Treg cell signature markers, and can selectively suppress autoreactive HLA-E+ TFH cells as well as tumor-induced CD4+ Treg cells. In contrast to FOXP3+ CD8+ Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E- . Adoptive transfer of this early-CD8+ Treg-like subset restrained tumor growth and inhibited CD4+ Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4+ Treg cells dominate the tumor-microenvironment, CD4+ Tregs mediate the clonal deletion of these tumor-suppressive FOXP3- IFNγ+ CD8+ CD25+ CD127- T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3- CD8+ CD25+ CD127- T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4+ Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.
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Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Vigilância Imunológica , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Modelos Biológicos , Neoplasias/patologia , Fenótipo , Receptores KIR/metabolismo , Evasão Tumoral , Microambiente TumoralRESUMO
This article has been withdrawn by the authors. A mistake was made during the preparation of Fig 1C, NKE panel. The Western blot data shown for p-ERK1/2 and actin are not from this set, but rather a similar set of data from a different experiment. The authors apologize to the readers.
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T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4+ Treg cells are well characterized whereas the role of CD8+ Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8+FOXP3+ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4+ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8+ Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8+ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8+ T cells. Whereas in CD8+ Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , DNA Intergênico/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Linfócitos T Reguladores/metabolismo , Transcrição Gênica , Adolescente , Adulto , Animais , Sequência de Bases , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Sequência Conservada/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Fator de Transcrição GATA3/metabolismo , Humanos , Terapia de Imunossupressão , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Modelos Genéticos , Proteína Smad3/metabolismo , Microambiente Tumoral , Adulto JovemRESUMO
Natural compounds obtained from plants are capable of garnering considerable attention from the scientific community, primarily due to their ability to check and prevent the onset and progress of cancer. These natural compounds are primarily used due to their nontoxic nature and the fewer side effects they cause compared to chemotherapeutic drugs. Furthermore, such natural products perform even better when given as an adjuvant along with traditional chemotherapeutic drugs, thereby enhancing the potential of chemotherapeutics and simultaneously reducing their undesired side effects. Curcumin, a naturally occurring polyphenol compound found in the plant Curcuma longa, is used as an Indian spice. It regulates not only the various pathways of the immune system, cell cycle checkpoints, apoptosis, and antioxidant response but also numerous intracellular targets, including pathways and protein molecules controlling tumor progression. Many recent studies conducted by major research groups around the globe suggest the use of curcumin as a chemopreventive adjuvant molecule to maximize and minimize the desired effects and side effects of chemotherapeutic drugs. However, low bioavailability of a curcumin molecule is the primary challenge encountered in adjuvant therapy. This review explores different therapeutic interactions of curcumin along with its targeted pathways and molecules that are involved in the regulation of onset and progression of different types of cancers, cancer treatment, and the strategies to overcome bioavailability issues and new targets of curcumin in the ever-growing field of cancer.