The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets

Science Translational Medicine, Год журнала: 2024, Номер 16(728)

Опубликована: Янв. 3, 2024

The extracellular matrix (ECM) is essential for cell support during homeostasis and plays a critical role in cancer. Although research often concentrates on the tumor’s cellular aspect, attention growing importance of cancer-associated ECM. Biochemical physical ECM signals affect tumor formation, invasion, metastasis, therapy resistance. Examining microenvironment uncovers intricate dysregulation interactions with cancer stromal cells. Anticancer therapies targeting sensors remodelers, including integrins metalloproteinases, ECM-remodeling cells, have seen limited success. This review explores ECM’s discusses potential therapeutic strategies cell-ECM interactions.

Язык: Английский

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Recent progress in targeted therapy for non-small cell lung cancer

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Фев. 21, 2023

The high morbidity and mortality of non-small cell lung cancer (NSCLC) have always been major threats to people’s health. With the identification carcinogenic drivers in clinical application targeted drugs, prognosis patients has greatly improved. However, a large number cases, driver is unknown. Identifying genetic alterations critical for effective individualized therapy NSCLC. Moreover, drugs are difficult apply clinic. Cancer drug resistance an unavoidable obstacle limiting efficacy drugs. This review describes mechanisms targeted-drug newly identified targets (e.g., KRAS G12C, NGRs, DDRs, CLIP1-LTK, PELP1, STK11/LKB1, NFE2L2/KEAP1, RICTOR, PTEN, RASGRF1, LINE-1, SphK1). Research into these will drive treatment generate better outcomes.

Язык: Английский

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Chemotherapy as a regulator of extracellular matrix-cell communication: Implications in therapy resistance

Seminars in Cancer Biology, Год журнала: 2022, Номер 86, С. 224 - 236

Опубликована: Март 21, 2022

Язык: Английский

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Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 66(1), С. 777 - 792

Опубликована: Дек. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Язык: Английский

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Extracellular Matrix Dynamics as an Emerging yet Understudied Hallmark of Aging and Longevity

Aging and Disease, Год журнала: 2023, Номер 14(3), С. 670 - 670

Опубликована: Янв. 1, 2023

The biomechanical properties of extracellular matrices (ECM) and their consequences for cellular homeostasis have recently emerged as a driver aging. Here we review the age-dependent deterioration ECM in context our current understanding aging processes. We discuss reciprocal interactions longevity interventions with remodeling. And relevance dynamics captured by matrisome matreotypes associated health, disease, longevity. Furthermore, highlight that many established compounds promote homeostasis. A large body evidence to qualify hallmark is emerging, data invertebrates promising. However, direct experimental proof activating sufficient slow mammals lacking. conclude further research required anticipate conceptual framework biomechanics will provide new strategies health during

Язык: Английский

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A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(6), С. e006720 - e006720

Опубликована: Июнь 1, 2023

Background Immune exclusion (IE) where tumors deter the infiltration of immune cells into tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported novel role discoidin domain-containing receptor 1 (DDR1) in promoting IE breast cancer and validated its critical using neutralizing rabbit monoclonal antibodies (mAbs) multiple mouse models. Methods To develop DDR1-targeting mAb potential therapeutic, we humanized mAb9 with complementarity-determining region grafting strategy. The antibody named PRTH-101 is currently being tested Phase clinical trial. determined binding epitope from crystal structure complex between DDR1 extracellular domain (ECD) Fab fragment 3.15 Å resolution. revealed mechanisms action both cell culture assays vivo study model. Results subnanomolar affinity to potent antitumor efficacy similar parental after humanization. Structural information illustrated that interacts (DS)-like domain, but not collagen-binding DS DDR1. Mechanistically, showed inhibited phosphorylation, decreased collagen-mediated attachment, significantly blocked shedding surface. Treatment tumor-bearing mice disrupted collagen fiber alignment (a physical barrier) matrix (ECM) enhanced CD8 + T tumors. Conclusions This only paves pathway for development also sheds light on new therapeutic strategy modulate ECM enhancing immunity.

Язык: Английский

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Progress in the treatment of diabetic cardiomyopathy, a systematic review

Pharmacology Research & Perspectives, Год журнала: 2024, Номер 12(2)

Опубликована: Фев. 26, 2024

Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, the absence of coronary artery disease, valve and other conventional cardiovascular risk factors such as hypertension dyslipidemia. It considered significant consequential complication diabetes field medicine. The primary pathological manifestations include hypertrophy, fibrosis, impaired ventricular function, which can lead to widespread necrosis. Ultimately, this progress development heart failure, arrhythmias, cardiogenic shock, severe cases even resulting sudden cardiac death. Despite several decades both fundamental clinical research conducted globally, there are currently no specific targeted therapies available for DCM practice, incidence mortality rates failure remain persistently high. Thus, article provides an overview current treatment modalities novel techniques pertaining DCM, aiming offer valuable insights support researchers dedicated investigating complex condition.

Язык: Английский

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Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma

Experimental Hematology and Oncology, Год журнала: 2024, Номер 13(1)

Опубликована: Фев. 22, 2024

Abstract Background Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on response HCC to immune checkpoint inhibitor (ICI) remains less clarified. Methods In silico, proteomic pathological assessment alteration were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation used evaluate cirrhotic-ECM’s effect ICI treatment. flow cytometry IHC explore how affect microenvironment. vitro vivo experiments carried out identify undermined Results We defined “a pro-tumor cirrhotic-ECM” was featured as up-regulation collagen type 1 (Col1). Cirrhotic-ECM/Col1 related impaired T cell function limited anti PD-1 (aPD-1) patients from TCGA pan cancer cohort authors’ institution, well multiple models. Mechanically, cirrhotic-ECM/Col1 orchestrated immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, initiated neutrophil traps (NETs) formation shield cells attacking impede approaching cells. Nilotinib, DDR1, reversed neutrophils/NETs dominant TME efficiently enhanced aPD-1. Conclusions Cirrhotic-ECM modulated a NETs enriched HCC, produced suppressive weakened efficiency. Col1 receptor DDR1 could be potential target synergically overcome mediated resistance. These provide mechanical insight novel strategy resistance HCC.

Язык: Английский

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Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis

Pharmacological Research, Год журнала: 2022, Номер 183, С. 106368 - 106368

Опубликована: Июль 26, 2022

Язык: Английский

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Collagen-induced DDR1 upregulates CXCL5 to promote neutrophil extracellular traps formation and Treg infiltration in breast cancer

International Immunopharmacology, Год журнала: 2023, Номер 120, С. 110235 - 110235

Опубликована: Май 16, 2023

Язык: Английский

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