Non-stem Cancer Cells Research Articles

MiR-29a-KLF4 signaling inhibits breast tumor initiation by regulating cancer stem cells

Cancer stem cells (CSCs) are known for their potent ability to drive tumor initiation and recurrence, yet the molecular mechanisms regulating CSCs are still unclear. Our study found a positive correlation between increased levels of miR-29a and better survival rates in early-stage breast cancer patients, but a negative correlation in late-stage patients, suggesting a dual function of miR-29a in regulating breast cancer. Furthermore, miR-29a showed significant downregulation in the ALDH+ breast cancer stem cell population compared to non-stem cancer cells. Overexpression of miR-29a in human breast cancer cells reduced the proportion of CSCs, suppressed their ability to form mammospheres, and inhibited the expression of stemness genes SOX2, KLF4, and hTERT in vitro. Conversely, knockdown of miR-29a in breast cancer cells showed opposite effects. Tumor xenograft experiments revealed that miR-29a overexpression significantly inhibited tumorigenesis initiated by MDA-MB-231 cell transplantation in nude mice. We further demonstrated that Krüppel-like factor 4 (KLF4), a key gene that regulates cell stemness, was a direct target of miR-29a in breast cancer cells. miR-29a suppressed the expression of KLF4 at both mRNA and protein levels. Reintroduction of KLF4 into breast cancer cells rescued the miR-29a-induced CSC suppression phenotype. In summary, our study is the first to demonstrate that miR-29a-KLF4 signaling inhibits breast tumor initiation by regulating CSCs, which provides novel therapeutic targets for preventing breast tumor initiation.

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells.

Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

Breast cancer stem cells generate immune-suppressive T regulatory cells by secreting TGFβ to evade immune-elimination

Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4+CD25+FOXP3+ T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4+CD25+FOXP3+ Treg cells from infiltrating CD4+ T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFNγ production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4+CD25+FOXP3+ Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGFβ, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4+CD25+FOXP3+ Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGFβ, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.

Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance.

Cancer stem cells (CSCs) are a rare cancer cell population, responsible for the facilitation, progression, and resistance of tumors to therapeutic interventions. This subset of cancer cells with stemness and tumorigenic properties is organized in niches within the tumor microenvironment (TME) and presents altered regulation in a variety of metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), as well as lipid, amino acid, and iron metabolism. CSCs exhibit similarities as well as differences when comparedto normal stem cells, but also possess the ability of metabolic plasticity. In this review, we summarize the metabolic characteristics of normal, non-cancerous stem cells and CSCs. We also highlight the significance and implications of interventions targeting CSC metabolism to potentially achieve more robust clinical responses in the future.

JMJD6–BRD4 complex stimulates lncRNA HOTAIR transcription by binding to the promoter region of HOTAIR and induces radioresistance in liver cancer stem cells

BackgroundLong non-coding RNA (lncRNA) HOTAIR acts importantly in liver cancer development, but its effect on radioresistance remains poorly understood. Here, our study probed into the possible impact of HOTAIR in radioresistance in liver cancer stem cells (LCSCs) and to elucidate its molecular basis.MethodsFollowing sorting of stem and non-stem liver cancer cells, LCSCs were identified and subjected to RNA-seq analysis for selecting differentially expressed genes. Expression of HOTAIR was determined in liver cancer tissues and CSCs. The stemness, proliferation, apoptosis and radioresistance of LCSCs were then detected in response to altered expression of HOTAIR-LSD1-JMJD6-BRD4.ResultsEctopic HOTAIR expression was found to promote radioresistance of LCSCs by maintaining its stemness. Mechanistic investigations indicated that HOTAIR recruited LSD1 to the MAPK1 promoter region and reduced the level of H3K9me2 in the promoter region, thus elevating ERK2 (MAPK1) expression. JMJD6–BRD4 complex promoted HOTAIR transcription by forming a complex and positively regulated ERK2 (MAPK1) expression, maintaining the stemness of LCSCs, and ultimately promoting their radioresistance in vitro and in vivo.ConclusionCollectively, our work highlights the promoting effect of the JMJD6–BRD4 complex on the radioresistance of LCSCs through a HOTAIR-dependent mechanism.

Ganoderma lucidum polysaccharides associated with 5-Fluorouracil impair OSCC tumorigenesis in vitro

BackgroundsGanoderma lucidum polysaccharides have been shown several anti-cancer, anti-inflammatory, and immunomodulatory properties among studies with different tumor models and its use with advanced and conventional combination therapies is a world trend. The administration of 5-Fluorouracil is already used as chemotherapy for many tumors and works on tumor remission; however, its adverse effects are still severe, impoverishing treatment and quality of life for patients. Cancer stem cells represent a subpopulation of cells with defense mechanisms against chemotherapy agents and are the main cause of relapses and metastases in cancer treatments. Also, the Epithelial-Mesenchymal Transition program increases properties related to tumor malignancy and mortality. In this scenario, the aim of the study is to evaluate the effects of Ganoderma lucidum polysaccharides in combination with 5-Fluorouracil on the subpopulation of cancer stem cells present in the human oral squamous carcinoma cell line SCC-9. MethodsSCC-9 cells were treated in vitro for 72 h with different 5-Fluorouracil low doses, associated or not with Ganoderma lucidum polysaccharides. Cells maintained with culture media or cisplatin were used as control. All the cells were evaluated for cytotoxicity, cancer stem cells, and Epithelial-Mesenchymal Transition properties. ResultsThe associated treatment avoided proliferation, delayed migration, slightly modified morphology of cells, increased apoptosis, decreased colony and blocked spheres formation, and downregulated cancer stem cells, Epithelial-Mesenchymal Transition, and ABC drug transporters expression. In addition, Ganoderma lucidum polysaccharides + 5-Fluorouracil changed the treated cells into a non-cancer stem cell phenotype, a characteristically not resistant and less proliferative population. The 5-Fluorouracil treatment alone showed remarkable modification in cellular morphology, apoptosis, and absence of holoclones; however, it upregulated the molecular expression of cancer stem cells' hallmarks. ConclusionsThese findings demonstrate that combining Ganoderma lucidum polysaccharides with a low dose of 5-Fluorouracil is effective against oral squamous cell carcinoma in vitro by enhancing the cells' sensitivity to drugs and reducing the characteristics associated with cancer stem cells (CSCs). This suggests the possibility of reducing conventional chemotherapy doses and improving oral squamous cell carcinoma treatment. It also highlights the potential for this combination to be used as an adjunct in Complementary Alternative Medicine (CAM).

The emerging role of the gut microbiome in cancer cell plasticity and therapeutic resistance.

Resistance to therapeutic agents is one of the major challenges in cancer therapy. Generally, the focus is given to the genetic driver, especially the genetic mutation behind the therapeutic resistance. However, non-mutational mechanisms, such as epigenetic modifications, and TME alteration, which is mainly driven by cancer cell plasticity, are also involved in therapeutic resistance. The concept of plasticity mainly relies on the conversion of non-cancer stem cells (CSCs) to CSCs or epithelial-to-mesenchymal transition via different mechanisms and various signaling pathways. Cancer plasticity plays a crucial role in therapeutic resistance as cancer cells are able to escape from therapeutics by shifting the phenotype and thereby enhancing tumor progression. New evidence suggests that gut microbiota can change cancer cell characteristics by impacting the mechanisms involved in cancer plasticity. Interestingly, gut microbiota can also influence the therapeutic efficacy of anticancer drugs by modulating the mechanisms involved in cancer cell plasticity. The gut microbiota has been shown to reduce the toxicity of certain clinical drugs. Here, we have documented the critical role of the gut microbiota on the therapeutic efficacy of existing anticancer drugs by altering the cancer plasticity. Hence, the extended knowledge of the emerging role of gut microbiota in cancer cell plasticity can help to develop gut microbiota-based novel therapeutics to overcome the resistance or reduce the toxicity of existing drugs. Furthermore, to improve the effectiveness of therapy, it is necessary to conduct more clinical and preclinical research to fully comprehend the mechanisms of gut microbiota.

Immune evasion by cancer stem cells ensures tumor initiation and failure of immunotherapy

Cancer stem cells (CSCs) are a small subpopulation of cells that drive the formation and progression of tumors. However, during tumor initiation, how CSCs communicate with neighbouring immune cells to overcome the powerful immune surveillance barrier in order to form, spread, and maintain the tumor, remains poorly understood. It is, therefore, absolutely necessary to understand how a small number of tumor-initiating cells (TICs) survive immune attack during (a) the “elimination phase” of “tumor immune-editing”, (b) the establishment of regional or distant tumor after metastasis, and (c) recurrence after therapy. Mounting evidence suggests that CSCs suppress the immune system through a variety of distinct mechanisms that ensure the survival of not only CSCs but also non-stem cancer cells (NSCCs), which eventually form the tumor mass. In this review article, the mechanisms via which CSCs change the immune landscape of the tissue of origin, which contains macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and tumor-infiltrating lymphocytes, in favour of tumorigenesis were discussed. The failure of cancer immunotherapy might also be explained by such interaction between CSCs and immune cells. This review will shed light on the critical role of CSCs in tumor immune evasion and emphasize the importance of CSC-targeted immunotherapy as a cutting-edge technique for battling cancer by restricting communication between immune cells and CSCs.

Antiproliferative Activities of Diterpenes from Leaves of Isodon trichocarpus against Cancer Stem Cells.

Two new diterpenes named trichoterpene I (1) and trichoterpene II (2) were isolated from the extract from the leaves of Isodon trichocarpus together with 19 known diterpenes. Their chemical structures were elucidated on the basis of chemical and physicochemical properties. Among them, oridonin (3), effusanin A (4), and lasiokaurin (9) with the α,β-unsaturated carbonyl moiety showed antiproliferative activities against breast cancer MDA-MB-231 and human astrocytoma U-251 MG cells [i.e., non-cancer stem cells (non-CSCs)] and their cancer stem cells (CSCs) isolated by sphere formation. In particular, compound 4 (IC50 = 0.51 µM) showed a higher antiproliferative activity against MDA-MB-231 CSCs than against MDA-MB-231 non-CSCs. The antiproliferative activity toward CSCs of compound 4 was equal to adriamycin (positive control, IC50 = 0.60 µM).

LncRNA H19-rich extracellular vesicles derived from gastric cancer stem cells facilitate tumorigenicity and metastasis via mediating intratumor communication network

BackgroundExtracellular vesicles (EVs) transport biologically active molecules, and represent a recently identified way of intercellular communication. Recent evidence has also reported that EVs shed by cancer stem cells (CSCs) make a significant contribution to carcinogenesis and metastasis. Here, this study aims to explore the possible molecular mechanism of CSCs-EVs in gastric cancer (GC) by mediating intratumor communication network.MethodsCSCs and non-stem cancer cells (NSCCs) were sorted from GC cells, and EVs were isolated from CSCs. H19 was knocked down in CSCs, and CSCs-EVs or CSCs-EVs containing shRNA-H19 (CSCs-EVs-sh-H19) were co-cultured with NSCCs, followed by evaluation of the malignant behaviors and stemness of NSCCs. Mouse models of GC were established and injected with CSCs-EVs from sh-H19-treated NSCCs in vivo.ResultsCSCs had notable self-renewal and tumorigenic capacity compared with NSCCs. CSCs promoted the malignant behaviors of NSCCs and expression of stemness marker proteins through secretion of EVs. Inhibited secretion of CSCs-EVs curtailed the tumorigenicity and metastasis of NSCCs in vivo. H19 could be delivered by CSCs-EVs into NSCCs. H19 promoted the malignant behaviors of NSCCs and stemness marker protein expression in vitro along with tumorigenicity and liver metastasis in vivo, which was mechanistically associated with activation of the YAP/CDX2 signaling axis.ConclusionTaken together, the present study points to the importance of a novel regulatory axis H19/YAP/CDX2 in carcinogenic and metastatic potential of CSCs-EVs in GC, which may be potential targets for anticancer therapy.

Optimized Method for Using Embryonic Microenvironment to Reprogram Cancer Stem Cells

Purpose: The embryonic microenvironment contains many properties that have not yet been fully explored. Our aim in this study is to report an optimized and efficient method that enables investigating the effects of the secretome of pluripotent embryonic stem cells on cancer stem cells.
 Methods: The study is performed with a chimeric model consisted of mouse blastocysts, human prostate cancer stem cells and non-cancer stem cells. Ovulation induced mice were used for blastocyst collection. DU145 prostate cancer cell line was separated into cancer stem cells and non-cancer stem cells according to cancer stem cells biomarker expressions by fluorescent activated cell sorting method. Human prostate cancer stem cells and non-cancer stem cells were microinjected into 4-day blastocyst culture in vitro by intracytoplasmic sperm injection method.
 Results: Chimeric models provide us great convenience in basic oncological studies. In this study, using a chimeric model, we were able to study the secretome of mouse embryonic stem cells and their effect on cancer stem cells. The method is efficient and yield promising result; and could be used to study the effects on other cells as well.
 Conclusion: The embryonic stem cell microenvironment is suggested to have a great regenerative capacity which is, nowadays, the center of attraction for cancer research studies. Ethical issues restrict the human embryo studies, however, mimicking the in vivo human microenvironment with 3D cell cultures or bioprinting are now possible. Finally, optimization of new methods including 3D cell cultures with human cell lines will be a great opportunity for better understanding the reprogramming notion.

Cancer Cell De-Differentiation: Plasticity-Driven Stratagem For Tumor Metastasis and Recurrence.

Tumor recurrence is a colossal challenge in clinical oncology. This multifactorial problem is attributed to the emergence of additional genetic mutations and the presence of dormant cancer cells. However, the plasticity of non-stem cancer cells and the acquisition of cancer stem cell (CSC) functionality is another contributing factor to tumor recurrence. Herein, I focus attention on the mechanisms that fuel cancer cell de-differentiation and the interplay between intra-cellular regulators and tumor microenvironment (TME) landscape that promotes cancer cell stemness. Our understanding of the mechanisms underlying tumor cell de-differentiation is crucial for developing innovative therapeutic strategies that prevent cancer from ever recurring.

On Fractional Order Model of Tumor Growth with Cancer Stem Cell

This paper generalizes the integer-order model of the tumour growth into the fractional-order domain, where the long memory dependence of the fractional derivative can be a better fit for the cellular response. This model describes the dynamics of cancer stem cells and non-stem (ordinary) cancer cells using a coupled system of nonlinear integro-differential equations. Our analysis focuses on the existence and boundedness of the solution in correlation with the properties of Mittag-Leffler functions and the fixed point theory elucidating the proof. Some numerical examples with different fractional orders are shown using the finite difference scheme, which is easily implemented and reliably accurate. Finally, numerical simulations are employed to investigate the influence of system parameters on cancer progression and to confirm the evidence of tumour growth paradox in the presence of cancer stem cells.

BIOM-22. BMX EXPRESSION LEVEL IN GLIOBLASTOMA PREDICTS HYPERSENSITIVITY TO IBRUTINIB TREATMENT

Abstract Glioblastoma (GBM) is the most prevalent and aggressive form of primary brain cancer and is notoriously drug and radiation resistant. The tumor recurrence and therapeutic resistance typically seen in GBM are largely driven by a small population of self-renewing, highly tumorigenic cells termed cancer stem cells (CSCs). The stem-cell-like properties of GBM CSCs are promoted, at least in part, by abnormal activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. This activation can occur through aberrant expression of bone marrow and X-linked (BMX) protein, a non-receptor tyrosine kinase that is upregulated in glioma stem cells and may be targeted by the drug ibrutinib, currently undergoing clinical trials in GBM. In contrast, BMX is not expressed in normal non-cancerous stem cells of the brain. We discovered a striking dissimilarity where a subset of our patient-derived GBM specimens are up to 100-fold more sensitive to ibrutinib than others. We investigated the mechanisms behind this hypersensitivity by analyzing the expression levels of JAK/STAT3 signaling proteins. Here we discovered that the baseline expression value of BMX prior to treatment has a strikingly high predictive value for later later response to ibrutinib, primarily explaining the variation in a specimen’s ibrutinib sensitivity. Furthermore, we found that pediatric GBM tumor models are typically BMX-low and most likely to be hypersensitive to ibrutinib compared to their adult counterparts. Ibrutinib further suppresses GBM and DIPG proliferation in CSC-rich proliferative regions of organoid models. Our data suggest the potential use of BMX as a predictive biomarker of ibrutinib sensitivity, and provide an impetus for mechanistic and preclinical investigation of ibrutinib sensitivity, particularly in pediatric disease.

On tumoural growth and treatment under cellular dedifferentiation

Differentiated cancer cells may regain stem cell characteristics; however, the effects of such a cellular dedifferentiation on tumoural growth and treatment are currently understudied. Thus, we here extend a mathematical model of cancer stem cell (CSC) driven tumour growth to also include dedifferentiation. We show that dedifferentiation increases the likelihood of tumorigenesis and the speed of tumoural growth, both modulated by the proliferative potential of the non-stem cancer cells (NSCCs). We demonstrate that dedifferentiation also may lead to treatment evasion, especially when a treatment solely targets CSCs. Conversely, targeting both CSCs and NSCCs in parallel is shown to be more robust to dedifferentiation. Despite dedifferentiation, perturbing CSC-related parameters continues to exert the largest relative effect on tumoural growth; however, we show the existence of synergies between specific CSC- and NSCC-directed treatments which cause superadditive reductions of tumoural growth. Overall, our study demonstrates various effects of dedifferentiation on growth and treatment of tumoural lesions, and we anticipate our results to be helpful in guiding future molecular and clinical research on limiting tumoural growth in vivo.

TGFB2-AS1 inhibits triple-negative breast cancer progression via interaction with SMARCA4 and regulating its targets TGFB2 and SOX2

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells invitro and dramatically decreases tumorigenic frequency and lung metastasis invivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including TGFB2 and SOX2 in an in cis or in trans way, leading to inhibition of transforming growth factor β (TGFβ) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFβ2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFβ2 in TNBC patients shows that high TGFB2-AS1 and low TGFβ2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.

Effect of Zoledronic Acid Treatment on Cell Adhesion Molecules in Prostate Cancer Stem Cells

Prostat kanserinin tanı ve tedavisine yönelik birçok alanda ilerleme sağlanabilmesine rağmen hastalık bazı vakalar için ölümcül olma niteliğini sürdürmektedir. Hastaların ölümden kurtulması için atılan her adım hedefe yaklaşılmasına yardım etse de halen sonuca ulaşmak için araştırılması gereken pek çok konu bulunmaktadır.
 Kök hücrenin keşfi ile bu hücrelerin insan sağlığı için önemi anlaşılmış ve tedavide nasıl kullanılacağının belirlenmesine yönelik çalışmalar büyük hız kazanmıştır. İlerleyen yıllarda Kanser Kök Hücresi kavramı ortaya çıkmış ve bu hücrelerin, kök hücre özelliklerini taşıyan ancak tümör dokusu içinde metastazı yapan, tedavi sonrası nükse yol açabilen veya tedaviye direnç̧ geliştiren hücreler oldukları belirlenmiştir. Köklülük özelliğine sahip bu hücreler dışında kalan hücre gurubu kanser kök hücresi olmayan hücre gurubudur ve konvansiyonel kanser tedavisine cevap veren kanser hücrelerdir. Kanserin metastaz yapması ve çevre dokuya invazyonunda adezyon moleküllerinin önemi büyüktür. Yapılan çalışmalar özellikle çoklu ilaç direnci ve epitelial mezenşimal geçişte adezyon moleküllerinin büyük önem kazandığını göstermiştir.
 Bu çalışmanın amacı prostat kanseri kök hücreleri üzerine zoledronik asit uygulaması sonrası, metastaz geliştirme sürecinde önemli rolü olan adezyon molekülleri üzerine etkisinin incelenmesidir. Bu amaçla DU145 insan prostat kanseri hücre hattından akım sitometri cihazı ile CD133/CD44 yüzey belirteçleri kullanılarak izole edilen kanser kök hücreleri üzerine zoledronik asit tedavisi uygulanmıştır. Kanser kök hücresinde oluşan değişiklikler adezyon molekülleri yönü ile araştırılmıştır. Elde edilen sonuçlar zoledronik asit tedavisi sonrası kanser kök hücresi sayısında önemli bir düşüş olduğunu ve bu uygulamanın CD44, ITGB1, CD29, LAMB1, LAMB3, LAMC1, SPP1, TGFB1, TGFB1, TIMP2, ADAMTS1, ITGB5’de önemli değişimlere yol açtığını göstermiştir. 
 Bu çalışmada in-vitro ortamda zoledronik asit uygulamasının kanser kök hücresi adezyon molekülleri üzerine baskılayıcı etki oluşturduğu ve ilerleyen çalışmalarda bu ilacın klinik kullanımda prostat kanseri tedavisinde uygulanabilme olasılığının olduğunu göstermiştir.

Abstract 2193: Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy

Abstract Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients’ demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1) and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients’ tumors. These rare CX3CR1High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1Low) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation. Citation Format: Jieyi Zhang, Anthony DiNatale, Ramanpreet Kaur, Qian Chen, Michael Marchioli, Darin Ipe, Maria Castelli, Christopher McNair, Gaurav Kumar, Olimpia Meucci, Alessandro Fatatis. Subsets of cancer cells expressing CX3CR1 are endowed with metastasis-initiating properties and resistance to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2193.

Differentiated glioma cell-derived fibromodulin activates integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth.

Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.