Adhesion Molecules in Multiple Myeloma Oncogenesis and Targeted Therapy

Zerdan, Maroun Bou; Nasr, Lewis; Kassab, Joseph; Saba, Ludovic; Ghossein, Myriam; Yaghi, Marita; Dominguez, Barbara; Chaulagain, Chakra P

doi:10.2217/ijh-2021-0017

Cited by 17 publications

(12 citation statements)

References 148 publications

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“…Fas-deletion recovers the loss of TAC T cell yield observed following MM.1S stimulation in the presence of 5 μM LCL161, which supports the hypothesis that the decline in T cell yield following stimulation with MM.1S is mediated, at least in part, through Fas signaling. Nevertheless, even in the absence of Fas, we do not observe an increase in TAC T cell viability or proliferation in the presence of LCL161, which suggests that LCL161-mediated costimulation is inconsequential in the presence of the full complement of adhesion molecules and costimulatory ligands (such as LFA-3 [ 40 )] found on the myeloma cells. Indeed, we have detected CD137L and CD86 on RPMI 8226 and MM.1S cells by flow cytometry (data not shown).…”

Section: Discussionmentioning

confidence: 75%

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

et al. 2023

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BackgroundThe genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics.MethodsWe have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology.ResultsLCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug’s effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161.ConclusionsOur results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.

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Section: Discussionmentioning

confidence: 75%

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

et al. 2023

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“…E-selectin promotes cancer metastatic behavior [ 30 ] and facilitates the adhesion of circulating tumor cells, leading to the preferential homing [ 31 ] and retention of metastatic cancer cells [ 32 ]. CD44, one of the E-selectin ligands expressed on migrating cancer cells [ 33 , 34 ], is known to interact with the soluble protein E-selectin in these processes [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Inflammation Control and Tumor Growth Inhibition of Ovarian Cancer by Targeting Adhesion Molecules of E-Selectin

Yang

Yin

Zhou

et al. 2023

Cancers

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Objective: The aim is to use E-selectin-binding peptide (ESBP) to actively recognize E-selectin, so allowing a drug delivery system to actively recognize the cells and inhibit the tumor growth of ovarian cancer by targeting adhesion molecules of E-selectin. An ovarian-cancer-directed drug delivery system was designed based on the high affinity of E-selectin-binding peptide (ESBP) to E-selectin. The effects and mechanisms of ESBP-bovine serum albumin (BSA) polymerized nanoparticles were investigated. Methods: BSA polymerized nanoparticles (BSANPs) and ESBP-BSANPs-paclitaxel (PTX) were prepared and their characteristics were measured. The in vitro targetability and cytotoxicity of ESBP-BSANPs-PTX were evaluated through in vitro drug uptake and MTT experiments. The mechanisms of ESBP-BSANPs-PTX were investigated via apoptosis, wound healing and immunohistochemistry assays. The in vivo targeting properties and drug effects were observed in a mouse tumor-bearing model. Results: In vitro experiments revealed an increase in the uptake of ESBP-BSANPs-FITC. The cytotoxicity of ESBP-BSANPs-PTX in A2780/CP70, HUVEC, RAW264.7 and ID8 cells was higher than that of PTX alone. ESBP-BSANPs-PTX increased cell apoptosis in a dose-dependent manner and exhibited a greater ability to inhibit cell migration than BSANPs-PTX. In vivo experiments demonstrated the targetability and good effects of ESBP-BSANPs. Conclusions: ESBP-BSANPs-PTX improve PTX targetability, provide tumor-specific and potent therapeutic activities, and show promise for the development of agents in preclinical epithelial ovarian cancer.

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“…The cell adhesion molecule ALCAM been reported to have an important role in tumor progression and is abundantly expressed in mesenchymal cells. Aberrant changes in ALCAM have also been reported in myeloma, prostate, esophagus, colon, pancreatic, and endometrial cancer [32,[45][46][47][48][49][50][51][52]. ALCAM is also a regulator of cadherin-mediated adherens junctions in uveal melanoma cells [53].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-214 expression by small molecules alleviates head and neck cancer metastasis by targeting ALCAM/TFAP2 signaling

Agarwal

Kansal

Farooqi

et al. 2023

Preprint

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Predominantly, head and neck cancer (HNC) is considered a regional disease and develops in the nasal cavity, oral cavity, tongue, pharynx, and larynx. In the advanced stage, the HNC spread into distant organs. By the time head and neck cancer diagnosed, the estimated metastasis is occurred in 10-40% cases. The most important vital organs affected by distant metastasis are the lungs, bones, and liver. Despite several advancements in chemotherapies, no significant changes are observed as 5-year survival rate remains the same. Therefore, it is crucial to decipher molecular mechanisms contributing to the metastatic dissemination of head and neck cancer. Here, we tested a novel ALCAM/TFAP2 signaling by targeting multidisciplinary miR-214 expression in head and cancer cells. Our results revealed that HNC cell lines (CAL27, SCC-9, SCC-4, and SCC-25) exhibit higher expression of miR-214 compared with normal human bronchial epithelial (NHBE) cells. Higher expression of miR-214 drives the invasive potential of these cell lines. Down-regulation of miR-214 in CAL27 and SCC-9 cells either using an anti-miR-214 inhibitor (50nM) or a small molecule of green tea (EGCG) inhibited cell invasion. Treating CAL27 and SCC-9 cells with EGCG also reduces ALCAM expression, a key activated leukocyte cell adhesion molecule, potentially blocking mesenchymal phenotype. Dietary administration of EGCG significantly inhibits distant metastasis of SCC-9 cells into the lungs, liver, and kidneys. Our results also demonstrate that the reduction of miR-214 expression influences in vitro cell movement and extravasation, as evident by reduced CD31 expression, a neovascularization marker. Together, these studies suggest that identifying bioactive molecules that can inhibit distant metastasis regulated by the miRNAs may provide potent interventional approaches and a better understanding of the complex functions of miRNAs and their therapeutic targets for clinical application.

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Adhesion Molecules in Multiple Myeloma Oncogenesis and Targeted Therapy

Cited by 17 publications

References 148 publications

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

Inflammation Control and Tumor Growth Inhibition of Ovarian Cancer by Targeting Adhesion Molecules of E-Selectin

Inhibition of miR-214 expression by small molecules alleviates head and neck cancer metastasis by targeting ALCAM/TFAP2 signaling

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