Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth

Abstract BackgroundThe release of Hsp70 chaperone from tumor cells is found to trigger the full-scale anti-cancer immune response. Such release and the proper immune reaction can be induced by the delivery of recombinant Hsp70 to a tumor and we sought to explore how the endogenous Hsp70 can be transported to extracellular space leading to the burst of anti-cancer activity. MethodsHsp70 transport mechanisms were studied by analyzing its intracellular tracks with Rab proteins as well as by using specific inhibitors of membrane domains. To study Hsp70 forms released from cells we employed the assay consisting of two affinity chromatography methods. Hsp70 content in culture medium and extracellular vesicles (EV) was measured with the aid of ELISA. The properties and composition of EVs were assessed using nanoparticle tracking analysis and immunoblotting. The activity of immune cells was studied using an assay of cytotoxic lymphocytes, and for in vivo studies we employed methods of affinity separation of lymphocyte fractions.Results Analyzing B16 melanoma cells treated with recombinant Hsp70 we found that the chaperone triggered extracellular transport of its endogenous analog in soluble and enclosed in EVs forms; both species efficiently penetrated adjacent cells and this secondary transport was corroborated with the strong increase of Natural Killer (NK) cell toxicity towards melanoma. When B16 and CT-26 colon cancer cells before their injection in animals were treated with Hsp70-enriched EVs, a powerful anti-cancer effect was observed as shown by a two-fold reduction in tumor growth rate and elevation of life span. We found that the immunomodulatory effect was due to the enhancement of the CD8-positive response and anti-tumor cytokine accumulation; supporting this there was no delay in CT-26 tumor growth when Hsp70-enriched EVs were grafted in nude mice. Importantly, pre-treatment of B16 cells with Hsp70-bearing EVs resulted in a decline of arginase-1-positive macrophages, showing no generation of tumor-associated macrophages. Conclusion In conclusion, Hsp70-containing EVs generated by specifically treated cancer cells give a full-scale and effective pattern of anti-tumor immune responses.

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IL‑21/IL‑21R inhibit tumor growth and invasion in non‑small cell lung cancer cells via suppressing Wnt/β‑catenin signaling and PD‑L1 expression

International Journal of Molecular Medicine ◽

10.3892/ijmm.2019.4354 ◽

2019 ◽

Author(s):

Dan Xue ◽

Ping Yang ◽

Qiongying Wei ◽

Xiaoping Li ◽

Lan Lin ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Inhibit Tumor Growth ◽

Small Cell Lung ◽

Tumor Growth And Invasion

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The ABCs of ovarian cancer immunology: IgA, B cells, and CTLs

Science Immunology ◽

10.1126/sciimmunol.abh3184 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabh3184

Author(s):

Andrew Lichtman

Keyword(s):

Ovarian Cancer ◽

B Cells ◽

Tumor Growth ◽

Cancer Cells ◽

Tumor Antigens ◽

Myeloid Cell ◽

Nonspecific Binding ◽

Inhibit Tumor Growth ◽

Ovarian Cancers ◽

Secreted Factors

Intratumoral B cells in ovarian cancers produce IgA, which binds tumor antigens and inhibit tumor growth through myeloid cell–dependent mechanisms or by neutralization of secreted factors, and by antigen-nonspecific binding to poly-Ig receptor on cancer cells leading to transcytosis, which sensitizes the cells for CTL killing.

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NSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo

IUBMB Life ◽

10.1002/iub.1035 ◽

2012 ◽

Vol 64 (7) ◽

pp. 636-643 ◽

Cited By ~ 16

Author(s):

Kristal Duncan ◽

Henriette Uwimpuhwe ◽

Akos Czibere ◽

Devanand Sarkar ◽

Towia A. Libermann ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Inhibit Tumor Growth

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Cancer-Associated Fibroblasts Promote Migration and Invasion of Non-Small Cell Lung Cancer Cells via miR-101-3p Mediated VEGFA Secretion and AKT/eNOS Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.764151 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xueru Guo ◽

Mengmeng Chen ◽

Limin Cao ◽

Yiming Hu ◽

Xueqin Li ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Small Cell ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Cancer Associated Fibroblasts ◽

Small Cell Lung ◽

Promoting Effect

Cancer-associated fibroblasts (CAFs) are major component of tumor microenvironment (TME), which plays crucial roles in tumor growth, invasion and metastasis; however, the underling mechanism is not fully elucidated. Despite many studies are focused on the tumor promoting effect of CAFs-derived cytokines, the upstream regulators of cytokine release in CAFs is largely unknown. Here we found that miR-101-3p was downregulated in primary lung cancer-associated CAFs compared to normal fibroblasts (NFs). Ectopic overexpression of miR-101-3p suppressed CAFs activation, and abrogated the promoting effect of CAFs on migration and invasion of non-small cell lung cancer cells (NSCLC), through attenuating CAFs’ effect on epithelial mesenchymal transition (EMT) process, metastasis-related genes (MMP9, TWIST1) and AKT/endothelial nitric oxide synthase (eNOS) signaling pathway. Further study indicated that vascular endothelial growth factor A (VEGFA) was a novel target of miR-101-3p, and CAFs-derived VEGFA mediated the effect of miR-101-3p on migration and invasion of lung cancer cells, demonstrated by using recombinant VEGFA and VEGFA neutralizing antibody. Interestingly, the analysis of the Cancer Genome Atlas (TCGA) database revealed that lung cancer tissues expressed lower level of miR-101-3p than non-cancerous tissues, and low/medium-expression of miR-101-3p was associated with poor overall survival (OS) rate. Moreover, the mouse xenograft experiment also showed that CAFs accelerated tumor growth whereas miR-101-3p diminished CAFs’ effect. These findings revealed a novel mechanism that CAFs facilitated lung cancer metastasis potential via miR-101-3p/VEGFA/AKT signaling pathway, suggesting miR-101-3p as a potential candidate for metastasis therapy.

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