Immuno-oncology: are TAM receptors in glioblastoma friends or foes?

AbstractTyro3, Axl, and Mertk (TAM) receptors are a subfamily of receptor tyrosine kinases. TAM receptors have been implicated in mediating efferocytosis, regulation of immune cells, secretion of inflammatory factors, and epithelial-to-mesenchymal transition in the tumor microenvironment, thereby serving as a critical player in tumor development and progression. The pro-carcinogenic role of TAM receptors has been widely confirmed, overexpression of TAM receptors is tied to tumor cells growth, metastasis, invasion and treatment resistance. Nonetheless, it is surprising to detect that inhibiting TAM signaling is not all beneficial in the tumor immune microenvironment. The absence of TAM receptors also affects anti-tumor immunity under certain conditions by modulating different immune cells, as the functional diversification of TAM signaling is closely related to tumor immunotherapy. Glioblastoma is the most prevalent and lethal primary brain tumor in adults. Although research regarding the crosstalk between TAM receptors and glioblastoma remains scarce, it appears likely that TAM receptors possess potential anti-tumor effects rather than portraying a total cancer-driving role in the context of glioblastoma. Accordingly, we doubt whether TAM receptors play a double-sided role in glioblastoma, and propose the Janus-faced TAM Hypothesis as a conceptual framework for comprehending the precise underlying mechanisms of TAMs. In this study, we aim to cast a spotlight on the potential multidirectional effects of TAM receptors in glioblastoma and provide a better understanding for TAM receptor-related targeted intervention.

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Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Cell Communication and Signaling ◽

10.1186/s12964-021-00739-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jillian Hattaway Luttman ◽

Ashley Colemon ◽

Benjamin Mayro ◽

Ann Marie Pendergast

Keyword(s):

Solid Tumors ◽

Tyrosine Kinases ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Effects ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Abl Kinases ◽

Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

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TAM Receptor Inhibition–Implications for Cancer and the Immune System

Cancers ◽

10.3390/cancers13061195 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1195

Author(s):

Pia Aehnlich ◽

Richard Morgan Powell ◽

Marlies J. W. Peeters ◽

Anne Rahbech ◽

Per thor Straten

Keyword(s):

T Cells ◽

Immune Responses ◽

Cancer Cells ◽

Immune Cells ◽

Tyrosine Kinases ◽

Apoptotic Cell ◽

Receptor Activation ◽

Mouse Tumor ◽

Oncogenic Signaling ◽

Tam Receptors

Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment.

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Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22095019 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5019

Author(s):

Helena Oliveres ◽

David Pesántez ◽

Joan Maurel

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Tyrosine Kinases ◽

Epithelial To Mesenchymal Transition ◽

Acquired Resistance ◽

Post Translational Modification ◽

Mesenchymal Transition ◽

Igf1r Signaling ◽

Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Journal of Oncology ◽

10.1155/2019/9681698 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alessandra Righetti ◽

Matteo Giulietti ◽

Berina Šabanović ◽

Giulia Occhipinti ◽

Giovanni Principato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Tumor Invasion ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Tumor Development ◽

Physiological Role ◽

Mesenchymal Transition ◽

Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation?

Cells ◽

10.3390/cells7070078 ◽

2018 ◽

Vol 7 (7) ◽

pp. 78 ◽

Cited By ~ 5

Author(s):

Julien Guinde ◽

Diane Frankel ◽

Sophie Perrin ◽

Valérie Delecourt ◽

Nicolas Lévy ◽

...

Keyword(s):

Lung Cancer ◽

Epithelial To Mesenchymal Transition ◽

Tumor Development ◽

Nuclear Lamina ◽

Metastatic Potential ◽

Disease Diagnosis ◽

Carcinoma Cells ◽

Scaffolding Protein ◽

Mesenchymal Transition ◽

Cancer Subtypes

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or metastatic cancers. In this context, the identification of new biomarkers is essential to improve the differential diagnosis between cancer subtypes, to select the most appropriate therapy, and to establish prognostic correlations. Nuclear abnormalities are hallmarks of carcinoma cells and are used as cytological diagnostic criteria of malignancy. Lamins (divided into A- and B-types) are localized in the nuclear matrix comprising nuclear lamina, where they act as scaffolding protein, involved in many nuclear functions, with regulatory effects on the cell cycle and differentiation, senescence and apoptosis. Previous studies have suggested that lamins are involved in tumor development and progression with opposite results concerning their prognostic role. This review provides an overview of lamins expression in lung cancer and the relevance of these findings for disease diagnosis and prognosis. Furthermore, we discuss the link between A-type lamins expression in lung carcinoma cells and nuclear deformability, epithelial to mesenchymal transition, and metastatic potential, and which mechanisms could regulate A-type lamins expression in lung cancer, such as the microRNA miR-9.

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Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

Current Molecular Medicine ◽

10.2174/1566524021666210202114844 ◽

2021 ◽

Vol 21 ◽

Author(s):

Kenneth Omabe ◽

Sandra Uduituma ◽

David Igwe ◽

Maxwell Omabe

Keyword(s):

Dna Damage ◽

Cancer Treatment ◽

Epithelial To Mesenchymal Transition ◽

Dna Damage Repair ◽

Treatment Resistance ◽

Therapy Resistance ◽

Cellular Reprogramming ◽

Repair System ◽

Mesenchymal Transition ◽

Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

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Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

Cell Death and Disease ◽

10.1038/s41419-020-2731-6 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

Author(s):

Xiuli Zhang ◽

Tingwen Guan ◽

Boxuan Yang ◽

Harvest F. Gu ◽

Zhihong Chi

Keyword(s):

Kidney Disease ◽

Pancreatic Beta Cells ◽

Diabetic Kidney Disease ◽

Epithelial To Mesenchymal Transition ◽

Gene Transfection ◽

Tubulointerstitial Fibrosis ◽

Inflammatory Factors ◽

Diabetic Kidney ◽

Mesenchymal Transition ◽

Tgf Β1

Abstract Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta-cells and ZnT8 dysfunction is involved in pathogenesis of diabetes. The current study aimed to investigate whether ZnT8 has effects in pathophysiology of diabetic kidney disease (DKD) by using animal models for diabetes, including STZ-induced diabetic, db/db, ZnT8-KO, ZnT8-KO-STZ and ZnT8-KO-db/db mice. Results demonstrated that urine albumin to creatinine ratio and epithelial-to-mesenchymal transition (EMT) were increased in kidneys of ZnT8-KO-STZ and ZnT8-KO-db/db mice compared with C57BL/6 J and ZnT8-KO mice, while serum TGF-β1, IL-6, and TNF-α levels were elevated in parallel. In kidneys of mice intercrossed between ZnT8-KO and STZ-induced diabetic or db/db mice, these three inflammatory factors, ACR and EMT were also found to be increased compared with C57BL/6J, db/db and ZnT8-KO mice. Furthermore, ZnT8 up-regulation by hZnT8-EGFP reduced the levels of high glucose (HG)-induced EMT and inflammatory factors in normal rat kidney tubular epithelial cell (NRK-52E cells). Expression of phosphorylated Smad2/Smad3 was up-regulated after HG stimulation and further enhanced by ZnT8 siRNA but down-regulated after hZnT8-EGFP gene transfection. The current study thus provides the first evidence that ZnT8 protects against EMT-tubulointerstitial fibrosis though the restrain of TGF-β1/Smads signaling activation in DKD.

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Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820459116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2237-2242 ◽

Cited By ~ 24

Author(s):

Eva A. Ebbing ◽

Amber P. van der Zalm ◽

Anne Steins ◽

Aafke Creemers ◽

Simone Hermsen ◽

...

Keyword(s):

Esophageal Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Treatment Resistance ◽

Serum Levels ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Dismal Prognosis ◽

Organoid Cultures

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.

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Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail

Cells ◽

10.3390/cells8030203 ◽

2019 ◽

Vol 8 (3) ◽

pp. 203 ◽

Cited By ~ 12

Author(s):

Jakub Kryczka ◽

Izabela Papiewska-Pajak ◽

M. Anna Kowalska ◽

Joanna Boncela

Keyword(s):

Cathepsin B ◽

Epithelial To Mesenchymal Transition ◽

Early Stage ◽

Tumor Development ◽

Colon Adenocarcinoma ◽

Mesenchymal Cell ◽

Tissue Samples ◽

Mesenchymal Transition ◽

Colon And Rectum ◽

Phenotypic Shift

During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures that accompany the mesenchymal migration. The invadosomes and their associated proteases restrict protease activity to areas of the cell in direct contact with the ECM, thus precisely controlling cell invasion. Our data prove that Snail-overexpressing HT-29 cells that imitate the phenotype of colon cancer cells in the early stage of the EMT showed an increase in the expression and pericellular activity of cathepsin B. It appears that the pericellular localization of cathepsin B, also observed in colon and rectum adenocarcinoma tissue samples, plays a key role in its function.

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Effect and Mechanism of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related Intestinal Fibrosis

Mediators of Inflammation ◽

10.1155/2021/5927064 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Jia Wenxiu ◽

Yang Mingyue ◽

Han Fei ◽

Luo Yuxin ◽

Wu Mengyao ◽

...

Keyword(s):

Transgenic Mice ◽

Tumor Necrosis ◽

Epithelial To Mesenchymal Transition ◽

Intestinal Inflammation ◽

Epithelial Mesenchymal Transition ◽

Lymphoid Cells ◽

Inflammatory Factors ◽

Mesenchymal Transition ◽

Intestinal Fibrosis

Background and Aims. Recent evidences reveal that epithelial to mesenchymal transition (EMT) exacerbates the process of intestinal fibrosis. Tumor necrosis factor-like ligand 1A (TL1A) is a member of the tumor necrosis family (TNF), which can take part in the development of colonic inflammation and fibrosis by regulating immune response or inflammatory factors. The purpose of this study was to elucidate the possible contribution of TL1A in onset and progression of intestinal inflammation and fibrosis through EMT. Methods. Colonic specimens were obtained from patients with inflammatory bowel disease (IBD) and control individuals. The expression levels of TL1A and EMT-related markers in intestinal tissues were evaluated. Furthermore, the human colorectal adenocarcinoma cell line, HT-29, was stimulated with TL1A, anti-TL1A antibody, or BMP-7 to assess EMT process. In addition, transgenic mice expressing high levels of TL1A in lymphoid cells were used to further investigate the mechanism of TL1A in intestinal fibrosis. Results. High levels of TL1A expression were detected in the intestinal specimens of patients with ulcerative colitis and Crohn’s disease and were negatively associated with the expression of an epithelial marker (E-cadherin), while it was positively associated with the expression of interstitial markers (FSP1 and α-SMA). Transgenic mice with high expression of TL1A were more sensitive to dextran sodium sulfate and exhibited severe intestinal inflammation and fibrosis. Additionally, the TGF-β1/Smad3 pathway may be involved in TL1A-induced EMT, and the expression of IL-13 and EMT-related transcriptional molecules (e.g., ZEB1 and Snail1) was increased in the intestinal specimens of the transgenic mice. Furthermore, TL1A-induced EMT can be influenced by anti-TL1A antibody or BMP-7 in vitro. Conclusions. TL1A participates in the formation and process of EMT in intestinal fibrosis. This new knowledge enables us to better understand the pathogenesis of intestinal fibrosis and identify new therapeutic targets for its treatment.

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