scholarly journals Inhibition of Post-Surgery Tumour Recurrence via a Sprayable Chemoimmunotherapy Gel Releasing PD-L1 Antibody and Platelet-Derived Exosomes

2021 ◽  
Author(s):  
Jian Zhao ◽  
Hao Ye ◽  
Qi Lu ◽  
Kaiyuan Wang ◽  
Xiaofeng Chen ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Tumour Cells ◽  
Tumour Recurrence ◽  
Fibrin Gel ◽  
Tumour Metastasis ◽  
Post Surgery ◽  
Local Tumour Recurrence ◽  
Local Tumour

Abstract Background: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods: Exosomes were isolated from platelets by differential centrifugation, and exosome-loaded doxorubicin (PexD) was prepared by mixing exosomes with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were coencapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion: Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence postsurgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

scholarly journals Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321187
Author(s):  
Songhe Guo ◽  
Jun Chen ◽  
Fangfang Chen ◽  
Qiuyao Zeng ◽  
Wan-Li Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumour Progression ◽  
Proteome Analysis ◽  
Fusobacterium Nucleatum ◽  
Tumour Cells ◽  
Migration Ability ◽  
Tumour Metastasis ◽  
Infected Cells

ObjectiveExosomes released from tumour cells are packed with unique RNA and protein cargo, and they are emerging as an important mediator in the communication network that promotes tumour progression. The facultative intracellular bacterium Fusobacterium nucleatum (Fn) is an important colorectal cancer (CRC)-associated bacterium. To date, the function of exosomes from Fn-infected CRC cells has not been explored.DesignExosomes were isolated by sequential differential centrifugation and verified by transmission electron microscopy, NanoSight analysis and Western blotting. Given that exosomes have been shown to transport miRNAs and proteins to alter cellular functions, we performed miRNA sequencing and proteome analysis of exosomes from Fn-infected and non-infected cells. The biological role and mechanism of exosomes from Fn-infected cells in CRC tumour growth and liver metastasis were determined in vitro and in vivo.ResultsWe demonstrated that exosomes delivered miR-1246/92b-3p/27a-3p and CXCL16/RhoA/IL-8 from Fn-infected cells into non-infected cells to increase cell migration ability in vitro and promote tumour metastasis in vivo. Finally, both circulating exosomal miR-1246/92b-3p/27a-3p and CXCL16 levels were closely associated with Fn abundance and tumour stage in patients with CRC.ConclusionThis study suggests that Fn infection may stimulate tumour cells to generate miR-1246/92b-3p/27a-3p-rich and CXCL16/RhoA/IL-8 exosomes that are delivered to uninfected cells to promote prometastatic behaviours.

scholarly journals Tumour cells express functional lymphatic endothelium-specific hyaluronan receptor in vitro and in vivo: Lymphatic mimicry promotes oral oncogenesis?

Oncogenesis ◽  
2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Sini Karinen ◽  
Krista Juurikka ◽  
Roosa Hujanen ◽  
Wafa Wahbi ◽  
Elin Hadler-Olsen ◽  
...  
Keyword(s):  
Tumour Cell ◽  
Lymphatic Metastasis ◽  
Tumour Cells ◽  
Metastatic Tumour ◽  
Tumour Metastasis ◽  
And Function ◽  
Cell Dissemination ◽  
Tumour Cell Dissemination

AbstractLymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC—lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin+/LYVE-1+, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.

Curative-intent radical en bloc resection using a minimum of a 3 cm margin in feline injection-site sarcomas: a retrospective analysis of 131 cases

2017 ◽  
Vol 20 (6) ◽  
pp. 509-519 ◽  
Author(s):  
Nina Müller ◽  
Martin Kessler
Keyword(s):  
Injection Site ◽  
Abdominal Wall ◽  
Retrospective Analysis ◽  
De Novo ◽  
Prognostic Significance ◽  
Tumour Cells ◽  
Tumour Recurrence ◽  
Curative Intent ◽  
Local Tumour Recurrence ◽  
Local Tumour

Objectives Owing to its highly infiltrative growth, feline injection-site sarcoma (FISS) carries a significant risk of local tumour recurrence. Parameters of possible prognostic significance (eg, tumour size and location, resection of de novo vs recurrent tumours, and achievement of tumour-free surgical margins) were examined with regard to their influence on recurrence rate (RR), disease-free interval (DFI) and survival time (ST). Methods This was a retrospective analysis of cats with FISSs located on the chest or abdominal wall or the interscapular region treated in a single institution using a standardised radical resection technique with 3 cm lateral margins and full-thickness body wall resection (tumours over chest/abdominal wall) or a minimum of two fascial planes (interscapular tumours). Results Median postoperative DFI and ST of 131 cats with FISSs was 21 and 24 months, respectively. Patients operated on for recurrent tumours were significantly more likely to die from tumour-related reasons compared with patients with de novo tumours ( P <0.001). RR and DFI in the different tumour locations were comparable ( P = 0.544 and P = 0.17, respectively). Local tumour recurrence occurred in 38.1% of the cats. Cats operated on for tumour recurrences had a significantly higher chance of another recurrence (RR 55.5% vs 33.3%; P = 0.005). Completeness of excision was determined by taking tumour bed biopsies. Tumour bed biopsies that did not contain tumour cells were associated with a significantly lower RR compared with those with tumour cells (30.5% vs 76.2%). Conclusions and relevance Depending on prognostic factors such as surgery for primary vs recurrent tumour, tumour-free resection margins and tumour location, the RR in FISS ranges from 33–55%, despite curative intent radical surgery. This study may help in identifying patients at risk for recurrence.

scholarly journals Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazim Husain ◽  
Domenico Coppola ◽  
Chung S. Yang ◽  
Mokenge P. Malafa
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Annexin V ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Sox2 Expression ◽  
Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

Mode of action of amphotericin B on chick embryo fibroblasts and on mouse Ehrlich tumour cells: a cytological and cytochemical analysis

1975 ◽  
Vol 18 (3) ◽  
pp. 441-451
Author(s):  
F. De Paermentier ◽  
R. Bassleer ◽  
A. Lepoint ◽  
C. Desaive ◽  
G. Goessens ◽  
...  
Keyword(s):  
Chick Embryo ◽  
Amphotericin B ◽  
Tumour Cells ◽  
Total Protein Content ◽  
Cell Multiplication ◽  
Cytochemical Analysis ◽  
Ehrlich Ascites ◽  
Embryo Fibroblasts

Chick embryo fibroblasts cultivated in vitro and Ehrlich ascites tumor cells (in vivo or in vitro) have been treated with amphotericin B. Cell multiplication is strongly inhibited. Large clear zones appear in the fibroblast nucleoi (phase-contrast and electron-microscope observations). Many treated fibroblasts and tumour cells have a high DNA content (pre-mitotic or polyploid level; measurements by cytophotometry). However, the RNA content (cytophotometry) and the total protein content (cytophotometry and micro-interferometry) are relatively low in the tumour cells. As shown by autoradiography, DNA synthesis is active but RNA synthesis and, in some cases, protein synthesis are inhibited. Due to this unbalanced growth, the cells cannot divide.

scholarly journals A Novel Kartogenin-Releasing Polymer Scaffold Promotes Wounded Rat Achilles Tendon Enthesis Healing

2018 ◽  
Vol 3 (3) ◽  
pp. 2473011418S0053
Author(s):  
Jianying Zhang ◽  
Daibang Nie ◽  
Guangyi Zhao ◽  
Susheng Tan ◽  
MaCalus Hogan ◽  
...  
Keyword(s):  
Achilles Tendon ◽  
Saline Group ◽  
Future Research ◽  
Dependent Manner ◽  
Polymer Scaffold ◽  
Normal Medium ◽  
Post Surgery ◽  
Tendon Stem Cells

Category: Hindfoot Introduction/Purpose: Entheses have a special fibrocartilage transition zone where tendons and ligaments attach to bone. Enthesis injury is very common, and the reattachment of tendon to bone is a great challenge because healing takes place between a soft tissue (tendon) and a hard tissue (bone). We have now developed a kartogene (KGN)-containing polymer scaffold (KGN-P) that can precisely deliver KGN to damaged enthesis area. The effects of the KGN-containing polymer on the healing of wounded TBJ were investigated in vitro and in vivo. Methods: The proliferation and chondrogenesis of rat Achilles tendon stem cells (TSCs) grown in four conditions were measured: normal medium (Control); normal medium with 100 nM KGN (KGN); lysine diisocyanate (LDI)-glycerol scaffold with normal medium (LDI-P); LDI-glycerol-KGN scaffold with normal medium (KGN-P).A wound (1 mm) was created on each hind leg Achilles enthesis of all 8 rats (3 months old). The wounds were then treated either with 10 ul saline (Wound); or 10 ul of 10 uM KGN (KGN); or LDI polymer scaffold (LDI-P); or KGN-containing polymer scaffold (KGN-P). The rats were sacrificed on day 15 and 30 post-surgery, and their Achilles entheses were collected for gross inspection and histochemical analysis. Results: KGN-containing polymers have sponge-like structures (Fig. 1A-D), and release KGN in a time- and temperature-dependent manner (Fig. 1E). KGN-P scaffold induced chondrogenesis of TSCs (Fig. 2D, 2H) without changing cell proliferation (Fig. 2I), and enhanced fibrocartilage-like tissue formation (Fig. 3E). KGN (Fig. 3C) and LDI-P (Fig. 3D) treated groups exhibited unhealed wound areas as in saline group (Fig. 3B). Finally, KGN-P and KGN treated rat TSCs underwent chondrogenesis by upregulating collagen II, aggrecan, and SOX-9 expression (Fig. 3F). Conclusion: Our results showed that KGN-containing polymer scaffold enhanced wounded enthesis healing by inducing TSC chondrogenesis and promoting the formation of the fibrocartilage in the wound site. The KGN-P may be used for regeneration of wounded entheses in clinical settings. Future research will focus on optimizing KGN concentration and releasing rate in the polymer scaffold during enthesis healing.

Hybrid Antibodies in Cancer Diagnosis and Therapy

1989 ◽  
Vol 4 (3) ◽  
pp. 131-134 ◽  
Author(s):  
S. Ménard ◽  
S. Canevari ◽  
M.I. Colnaghi
Keyword(s):  
Tumor Cell ◽  
Cancer Diagnosis ◽  
Cytotoxic T Cells ◽  
Lymphocyte Activation ◽  
Cytotoxic Agents ◽  
Toxic Agent ◽  
In Vivo Models ◽  
Promising Tool

Monoclonal Antibodies (Mabs) represent a promising tool for cancer diagnosis and theraphy. Administration of MAbs alone or conjugated to cytotoxic agents has been attempted but has significant limitations. Another potentially effective approach is the use of bispecific or bifunctional antibodies where the capacity to recognize the tumor cell and the toxic agent or lymphocyte activation molecule are united in one MAb. The hybrid molecule can be produced by chemical linkage between the two parentalantibodies, or alternatively by a biological approach that consists in the fusion of the two selected hybridomas. In the resulting quadroma cell the hybridoma immunoglobulin chains recombine randomly to form the bifunctional MAb. In different in vitro and in vivo models, bifunctional MAbs against tumor and CDS at nanomolar concentration has been shown to promote tumor cell killing by cytotoxic T cells. Specific localization of chemotherapeutic drugs in xenografted tumors has been demonstrated in mice pretreated with hybrid MAbs. The advantages of the hybrid MAb approach are that it should reduce the MAb biodistribution problem and that it involves no chemical manipulation between the functional agent and the MAb molecules.

scholarly journals Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Yujun Tang ◽  
Yishi Lu ◽  
Yuan Chen ◽  
Lei Luo ◽  
Lei Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Line ◽  
Lentiviral Vector ◽  
Tumour Cells ◽  
Clinical Samples ◽  
Circulating Tumour Cells ◽  
Metastatic Niche ◽  
Metastatic Sites

Abstract Background Circulating tumour cells (CTCs), especially mesenchymal CTCs, are important determinants of metastasis, which leads to most recurrence and mortality in hepatocellular carcinoma (HCC). However, little is known about the underlying mechanisms of CTC colonisation in pre-metastatic niches. Methods Detection and classification of CTCs in patients were performed using the CanPatrol™ system. A lentiviral vector expressing Prrx1-targeting shRNA was constructed to generate a stable HCC cell line with low expression of Prrx1. The effect of Prrx1 knockdown on stemness, migration, and drug resistance of the cell line was assessed, including involvement of SDF-1/CXCR4 signalling. Promising clinical applications of an inhibitor of STAT3 tyrosine phosphorylation, C188–9, and specific blockade with CXCR4 antibody were explored. Results The number of mesenchymal CTCs in blood was closely associated with tumour recurrence or metastasis. Pre-metastatic niche-derived SDF-1 could downregulate Prrx1, which induced the stemness, drug resistance, and increased expression of CXCR4 in HCC cells through the STAT3 pathway in vitro. In vivo, mice bearing tumours of Prrx1 low-expressing cells had significantly shorter survival. In xenograft tumours and clinical samples, loss of Prrx1 was negatively correlated with increased expression of CXCR4 in lung metastatic sites compared with that in the primary foci. Conclusions These findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC. STAT3 inhibition and specific blockade of CXCR4 have clinical potential as therapeutics for eliminating organ metastasis in advanced HCC.

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