Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell–derived IL-6 is reversed predominantly by IL-6 blockade

Antoon, Roula; Wang, Xinghua; Saleh, Amr H.; Warrington, Jenny; Hedley, David W.; Keating, Armand

doi:10.1016/j.jcyt.2021.12.005

Cited by 9 publications

(8 citation statements)

References 55 publications

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“…Also, IL-6 trans-signaling is constitutively active in several pancreatic cancer (PC) cell lines [ 53 ]. Thus, in vitro blocking of IL-6R signaling by TCZ showed pSTAT3 downregulation and inhibition of IL-6 expression in both pancreatic cancer cells and mesenchymal stem cells (MSCs) [ 54 ]. Also, enhanced IL-6 expression was positively correlated with lymph node metastasis, tumor differentiation, and vascular invasion in PC patients [ 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Groza,

Lacina,

Kuchař

et al. 2024

Cell Commun Signal

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Background Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target. Methods An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking. Results We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells. Conclusion We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.

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Section: Discussionmentioning

confidence: 99%

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Groza,

Lacina,

Kuchař

et al. 2024

Cell Commun Signal

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“…Although there is still controversy surrounding the ability of MSCs to induce tumors, some studies have indicated that MSCs can indeed induce both tumor development and metastasis [ 38 , 39 ]. The developers of cell therapy products are required to conduct tumor-promoting tests and consult with regulators.…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

Wu,

Ma,

Yang

et al. 2023

Stem Cell Res Ther

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Background Safety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically defined media (S&XFM–CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM–CD (UCMSCS&XFM−CD) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSCSCM). However, a comprehensive investigation of the safety of intraperitoneal UCMSCS&XFM−CD treatment should be performed before clinical applications. Methods In this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSCS&XFM−CD were compared with UCMSCSCM in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSCS&XFM−CD were compared with UCMSCSCM in nude mice. Results We confirmed that intraperitoneally transplanted UCMSCS&XFM−CD or UCMSCSCM did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSCS&XFM−CD did not produce antibodies, while UCMSCSCM had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSCS&XFM−CD were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSCSCM. In addition, UCMSCS&XFM−CD or UCMSCSCM showed no obvious tumorigenic activity. Finally, UCMSCS&XFM−CD extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSCSCM. Conclusions Taken together, our data indicate that UCMSCS&XFM−CD display an improved safety performance and are encouraged to use in future clinical trials.

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“…BMMSCs promote metastasis by activating the ABL–MMP9 signaling axis in lung cancer cells ( 42 ). BMMSCs secreted IL-6 contribute significantly to pancreatic cancer growth ( 43 ). However, BMMSCs-derived IL-28 trigger prostate cancer cell apoptosis via IL-28Rα–STAT1 signaling pathway ( 44 ).…”

Section: Regulatory Effects Of Mscs From Different Sources On Tumor C...mentioning

confidence: 99%

Mesenchymal stem/stromal cells- a principal element for tumour microenvironment heterogeneity

Sun,

Yao

2023

Front. Immunol.

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The heterogeneity of the tumor microenvironment (TME) is a major obstacle in cancer treatment, making most therapeutic interventions palliative rather than curative. Previous studies have suggested that the reason for the low efficacy of immunotherapy and the relapse of the original responders over time may be due to the complex network of mesenchymal stem/stromal cells (MSCs), a population of multipotent progenitor cells existing in a variety of tissues. Cancer-associated MSCs (CA-MSCs) have already been isolated from various types of tumors and are characterized by their vigorous pro-tumorigenic functions. Although the roles of CA-MSCs from different sources vary widely, their origins are still poorly understood. Current evidence suggests that when local resident or distally recruited MSCs interact with tumor cells and other components in the TME, “naïve” MSCs undergo genetic and functional changes to form CA-MSCs. In this review, we mainly focus on the multiple roles of CA-MSCs derived from different sources, which may help in elucidating the formation and function of the entire TME, as well as discover innovative targets for anti-cancer therapies.

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Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell–derived IL-6 is reversed predominantly by IL-6 blockade

Cited by 9 publications

References 55 publications

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

Mesenchymal stem/stromal cells- a principal element for tumour microenvironment heterogeneity

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