Targeting the Microenvironment Niche in Solid and Hematologic Malignancies: Basic and Translational Research

Editors

Unit of Hematology, Department of Health Promotion, Maternal-Infant, Internal and Specialized Medicine of Excellence G. D'Alessandro, University of Palermo

Marco Rossi

University Hospital Renato Dulbecco

Niccolò Bolli

University of Milan

Niels Weinhold

Heidelberg University

Impact

Original Research

06 May 2021

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy

Jian Hu

, 7 more and

Xiongbing Zu

Background: YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown.

Methods: All original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database.

Results: In general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation.

Conclusion: YTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.

22,812 views

99 citations

(A) HOTAIRM1 expression was analyzed by qRT-PCR in t-FB1/2 transfected with shNC, shHOTAIRM1-1, or shHOTAIRM1-2. **p < 0.01, one-way ANOVA. (B–D) Proliferation ability was evaluated after HOTAIRM1 downregulation in t-FB1/2 using EdU assay. *p < 0.05, **p < 0.01, one-way ANOVA. (E, F) Invasion capacity was measured after HOTAIRM1 downregulation in t-FB1/2 by transwell assay. *p < 0.05, **p < 0.01, one-way ANOVA. (G–J) Migration capacity was detected after downregulation of HOTAIRM1 in t-FB1/2 by wound healing assay. **p < 0.01, one-way ANOVA. (K, N) Tumorigenicity assay performed in nude mice by subcutaneous inoculation of t-FB1/2 cells transfected with shNC, shHOTAIRM1-1, or shHOTAIRM1-2, respectively. (L, M, O, P) Tumor growth curve and tumor weight of shNC, shHOTAIRM1-1, and shHOTAIRM1-2 group. ****p < 0.0001, two-way ANOVA; *p < 0.05, **p < 0.01, ***p < 0.001, one-way ANOVA.

Original Research

19 March 2021

HOTAIRM1 Promotes Malignant Progression of Transformed Fibroblasts in Glioma Stem-Like Cells Remodeled Microenvironment via Regulating miR-133b-3p/TGFβ Axis

Haiyang Wang

, 8 more and

Jun Dong

3,258 views

17 citations

Western blots showing LRIG3, p-AKT, AKT, p-ERK, ERK, and VEGFA (A) alongside GAPDH (B) in the indicated glioma cells treated with the pathway inhibitors LY294002 (25μM), PD98059 (10μM), or DMSO vehicle for 24 h. (C) Levels of VEGFA protein in the CM from the indicated glioma cells were detected by ELISA. (D) Transwell migration assays in HUVECs treated with the indicated CM. (E) HUVECs formed tube-like structures with the indicated CM. (F) Cell viability of HUVECs was determined using the MTT assay. HUVECs were treated with the CM derived from the indicated cells for the specific number of days. Data are means ± SD of 3 independent replicates. *p < 0.05; **p < 0.01; ***p < 0.001; #p < 0.05, siLRIG3 + LY294002 versus siLRIG3 + vehicle and siLRIG3 + PD98059; ##p < 0.01, siLRIG3 + LY294002 versus siLRIG3 + vehicle and siLRIG3 + PD98059. CM, conditioned medium.

Original Research

25 February 2021

LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma

Chenghao Peng

, 8 more and

Dongsheng Guo

4,551 views

18 citations

Intracellular entry of AAT occurs constitutively based on lipid raft independent pathways, namely clathrin-mediated, or lipid rafts-dependent, which include caveolae- and flotilin-dependent endocytosis. The AAT could be sequestered into clathrin-coated pits by binding to LRP1 (low-density lipoprotein receptor related protein 1) and SR-BI (scavenger receptor class b type I). Alternatively, AAT can associate with caveolin or flotilin 1/2-postive lipid rafts. All entry pathways might generate AAT-containing vesicles fusing with early endosomes and lysosomes from which—by unknown mechanisms - AAT escapes into the cytoplasm (green structure). There, AAT could affect cancer cell responses to cytotoxic drugs, like STS (staurosporine). STS activates autophagy by inhibiting mTOR (mammalian target of rapamycin), which allows Beclin-1/PI 3-kinase complex formation, increases LC3-II/LC3-I ratio, p62 degradation in autolysosomes and downregulation of Fli I (Flightless I), a controller of p62-LC3 interaction. Indeed, AAT seems to block different steps required for STS to induce autophagy. Potentially, AAT may also interfere with Atg5-Atg12 complex required for the formation of autophagosomes or recruitment of LC-3 to autophagosomes (green structures). As an inducer of apoptosis, STS acts through the activation of the mitochondrial apoptotic pathway. STS causes the aggregation of Bax/Bak and the release of cytochrome c that binds to Apaf-1 (apoptotic protease-activating factor 1) allowing apoptosome assembly and the recruitment of procaspase-9 to the apoptosome. In this scenario AAT might inhibit activation of procaspases-8, -9, -3 preventing Beclin-1/Atg5 degradation and activation of CAD (caspase-activated DNase). A crosstalk between STS-induced autophagy and apoptosis is in part mediated by p62 and beclin-1. Finding that AAT by itself strongly reduces p62 levels but prevents p62 reduction in STS-treated cells suggests that cancer cells utilize AAT to regulate apoptosis and autophagy dependent on the situation. Under basal conditions, AAT as a reducer of p62 protein levels (also important for the activation of procaspase-8), might activate autophagy as a cytoprotective pathway. In the setting when cancer cells face pro-apoptotic activation, autophagy inhibition may become a strategy to escape apoptosis.

Mini Review

19 February 2021

Potential Roles of Acute Phase Proteins in Cancer: Why Do Cancer Cells Produce or Take Up Exogenous Acute Phase Protein Alpha1-Antitrypsin?

Sabina Janciauskiene

, 4 more and

Tobias Welte

5,963 views

25 citations

(A) Representative images of human macrophages (red) phagocytosing Raji cells (green) following treatment with the 10 μg/ml indicated antibodies or not. Scale bar, 50 μm. (B) Representative images of mouse macrophages (red) phagocytosing Raji cells (green) following treatment with the 10 μg/ml indicated antibodies or not. Scale bar, 50 μm. (C) Mouse macrophages phagocytose Raji cells in the presence of 2C8 or B6H12.2 in a concentration-dependent manner. (D) Bar graph demonstrating the change of phagocytosis rates by mouse M0, M1, and M2 macrophages toward Raji cells in the presence of 10 μg/ml 2C8 or 10 μg/ml B6H12.2. (E) In vitro phagocytosis of multiple tumor cells by mouse macrophages in the presence of 10 μg/ml 2C8 or 10 μg/ml B6H12.2. The data are represented as mean ± SEM. (****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05, multiple t tests). The experiment was performed three times with similar results.

Original Research

05 January 2021

A Novel Blockade CD47 Antibody With Therapeutic Potential for Cancer

Fangzhen Lin

, 13 more and

Dongsheng Xiong

14,345 views

24 citations

Review

06 January 2021

Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy

Ramiro Vázquez

, 7 more and

L’Houcine Ouafik

8,411 views

25 citations

Original Research

15 February 2021

Pictilisib Enhances the Antitumor Effect of Doxorubicin and Prevents Tumor-Mediated Bone Destruction by Blockade of PI3K/AKT Pathway

Chao Liang

, 4 more and

Yang Dong

4,507 views

12 citations

Original Research

12 February 2021

P. aeruginosa Mediated Necroptosis in Mouse Tumor Cells Induces Long-Lasting Systemic Antitumor Immunity

Jia-long Qi

, 5 more and

Yan-bing Ma

2,752 views

14 citations

MSLN elevation activates MAPK/ERK, PI3K/Akt pathways therefore making cancer cells resistant to apoptosis. Also, MSLN overexpression induces NF-kB which leads to higher IL-6 production. High IL-6 induces the transcription protein 3 (Stat3), resulting in increased expression levels of the cyclin E/cyclin-dependent kinase (CDK2) complex, therefore speeding the G1-S transition resulting in enhanced cell proliferation.

Review

04 December 2020

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

Nada H. Hussein

, 1 more and

Hend M. El Tayebi

8,973 views

14 citations

Molecular mechanisms for the tumor promoting actions of adrenergic signals.

Mini Review

13 May 2020

The Autonomic Regulation of Tumor Growth and the Missing Links

Maricris Bautista

and

Anand Krishnan

4,365 views

18 citations

NLGP downregulates VEGF expression in tumor, cultured cancer cells and immune cells. (A) Immunohistochemical expression of VEGF in untreated and NLGP treated murine B16Mel tumor tissue. (B) Representative figures from tumor bearing (n = 6) hosts are presented in 20X and 40X magnification. Intensity of staining in six different fields from tumor sections of untreated and NLGP treated mice. Mean ± SD of staining intensity of VEGF are also shown. (C) Tumors from untreated and NLGP treated (1.5 μg/ml) C57BL6/J mice were cryosectioned and mRNA expression of cd11c, cd11b, gp100 genes after laser capture microdissection of VEGF positive zones were measured using RT-PCR, keeping β-actin as loading control. (D) A bar diagram represents the mean ± SD of relative expression of respective genes (n = 4). (E) Expression of vegf gene is shown in B16Mel, LLC and macrophages cultured in both normoxic and hypoxic conditions (6 h of NLGP and hypoxia exposure) (n = 6 for each cell type), keeping β-actin as loading control. (F) Bar diagrammatic representation show mean ± SD of relative expression of vegf from all untreated and NLGP treated cell lines. (G) A bar diagram showing mean ± SD (n = 6) of VEGF levels as measured by ELISA in B16Mel, LLC and macrophage cells obtained from both hypoxic and normoxic conditions, w/wo NLGP. Cells were pre-treated for 48 h in NLGP and kept in 12 h hypoxia. P-values showing significance of difference are indicated in respective bar diagrams.

Original Research

06 March 2020

Neem Leaf Glycoprotein Restrains VEGF Production by Direct Modulation of HIF1α-Linked Upstream and Downstream Cascades

Akata Saha

, 8 more and

Anamika Bose

3,686 views

13 citations

Original Research

10 January 2020

Prognostic and Immunological Role of FUN14 Domain Containing 1 in Pan-Cancer: Friend or Foe?

Qingchen Yuan

, 6 more and

Xiao Chen

Background: FUN14 domain containing 1 (FUNDC1) plays a pivotal role in mitochondrial autophagy (mitophagy), which is closely associated with human immunity. However, the role of FUNDC1 in cancers remains unclear. This study aimed to visualize the prognostic landscape of FUNDC1 in pan-cancer and investigate the relationship between FUNDC1 expression and immune infiltration.

Methods: In this study, we explored the expression pattern and prognostic value of FUNDC1 in pan-cancer across multiple databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, using the GEPIA and TIMER databases, we investigated the correlations between FUNDC1 expression and immune infiltration in cancers, especially liver hepatocellular carcinoma (LIHC), and lung squamous cell carcinoma (LUSC).

Results: In general, compared with that in normal tissue, tumor tissue had a higher expression level of FUNDC1. Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients. Although different from what was found for LUSC, for LIHC, there were significant positive correlations between FUNDC1 expression and immune infiltrates, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages, and dendritic cells. Furthermore, markers of infiltrating immune cells, such as tumor-associated-macrophages (TAMs), exhibited different FUNDC1-related immune infiltration patterns.

Conclusion: The mitophagy regulator FUNDC1 can serve as a prognostic biomarker in pan-cancer and is correlated with immune infiltrates.

16,784 views

48 citations

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