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Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and...
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Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 October 2024) | Viewed by 14509

Special Issue Editor

Prof. Dr. Carl-Henrik Heldin

E-Mail Website
Guest Editor
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Interests: growth factors; signal transduction mechanisms; receptors; kinases; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Members of the family of receptor tyrosine kinases (RTKs) have been shown to have important functions in embryonal development, wound healing, and tissue homeostasis. Based on their structural properties, the 58 members of the family can be divided in 20 subfamilies; their extracellular ligand-binding parts are composed of different combinations of domains, including immunoglobulin-like, epidermal growth factor-like, fibronectin-like, cysteine-rich, cadherin-like, and discoidin-like domains, and their intracellular parts contain intrinsic tyrosine-kinase domains.

Many, maybe all, RTKs are activated by dimerization or oligomerization, induced by ligand binding. This results in the auto-phosphorylation of certain tyrosine residues in the intracellular parts of the receptors, creating docking sites for SH2-domain-containing molecules, as well as in the tyrosine phosphorylation of specific downstream signaling molecules. The activated signaling pathways leads to the stimulation of cell growth, survival, and migration. Over-activity, by mutation, amplification, or overexpression, of RTKs are common in tumorigenesis, and more than half of the known RTKs have been implicated as drivers of various types of tumors. Tyrosine kinase inhibitors have therefore been developed and are used clinically, with beneficial effects in the treatment of certain tumors.

This Special Issue will highlight recent developments in our understanding about the normal function of RTKs and their role in disease, as well as their structural properties.

Prof. Dr. Carl-Henrik Heldin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • receptor
  • tyrosine kinase
  • growth factor
  • signal transduction
  • development
  • regeneration
  • tumorigenesis

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Published Papers (6 papers)

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Research

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20 pages, 4464 KiB  
Article
IGF1R Contributes to Cell Proliferation in ALK-Mutated Neuroblastoma with Preference for Activating the PI3K-AKT Signaling Pathway
by Jikui Guan, Marcus Borenäs, Junfeng Xiong, Wei-Yun Lai, Ruth H. Palmer and Bengt Hallberg
Cancers 2023, 15(17), 4252; https://doi.org/10.3390/cancers15174252 - 25 Aug 2023
Cited by 5 | Viewed by 1838
Abstract
Aberrant activation of anaplastic lymphoma kinase (ALK) by activating point mutation or amplification drives 5–12% of neuroblastoma (NB). Previous work has identified the involvement of the insulin-like growth factor 1 receptor (IGF1R) receptor tyrosine kinase (RTK) in a wide range of cancers. We [...] Read more.
Aberrant activation of anaplastic lymphoma kinase (ALK) by activating point mutation or amplification drives 5–12% of neuroblastoma (NB). Previous work has identified the involvement of the insulin-like growth factor 1 receptor (IGF1R) receptor tyrosine kinase (RTK) in a wide range of cancers. We show here that many NB cell lines exhibit IGF1R activity, and that IGF1R inhibition led to decreased cell proliferation to varying degrees in ALK-driven NB cells. Furthermore, combined inhibition of ALK and IGF1R resulted in synergistic anti-proliferation effects, in particular in ALK-mutated NB cells. Mechanistically, both ALK and IGF1R contribute significantly to the activation of downstream PI3K-AKT and RAS-MAPK signaling pathways in ALK-mutated NB cells. However, these two RTKs employ a differential repertoire of adaptor proteins to mediate downstream signaling effects. We show here that ALK signaling led to activation of the RAS-MAPK pathway by preferentially phosphorylating the adaptor proteins GAB1, GAB2, and FRS2, while IGF1R signaling preferentially phosphorylated IRS2, promoting activation of the PI3K-AKT pathway. Together, these findings reveal a potentially important role of the IGF1R RTK in ALK-mutated NB and that co-targeting of ALK and IGF1R may be advantageous in clinical treatment of ALK-mutated NB patients. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
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10 pages, 245 KiB  
Article
Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations
by Yaser Gamallat, Mitra Afsharpad, Soufiane El Hallani, Christopher A. Maher, Nimira Alimohamed, Eric Hyndman and Tarek A. Bismar
Cancers 2023, 15(12), 3167; https://doi.org/10.3390/cancers15123167 - 13 Jun 2023
Viewed by 1279
Abstract
The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including [...] Read more.
The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
20 pages, 3622 KiB  
Article
PRAME Is a Novel Target of Tumor-Intrinsic Gas6/Axl Activation and Promotes Cancer Cell Invasion in Hepatocellular Carcinoma
by Viola Hedrich, Kristina Breitenecker, Gregor Ortmayr, Franziska Pupp, Heidemarie Huber, Doris Chen, Sarthak Sahoo, Mohit Kumar Jolly and Wolfgang Mikulits
Cancers 2023, 15(9), 2415; https://doi.org/10.3390/cancers15092415 - 22 Apr 2023
Cited by 9 | Viewed by 3356
Abstract
(1) Background: Activation of the receptor tyrosine kinase Axl by Gas6 fosters oncogenic effects in hepatocellular carcinoma (HCC), associating with increased mortality of patients. The impact of Gas6/Axl signaling on the induction of individual target genes in HCC and its consequences is an [...] Read more.
(1) Background: Activation of the receptor tyrosine kinase Axl by Gas6 fosters oncogenic effects in hepatocellular carcinoma (HCC), associating with increased mortality of patients. The impact of Gas6/Axl signaling on the induction of individual target genes in HCC and its consequences is an open issue. (2) Methods: RNA-seq analysis of Gas6-stimulated Axl-proficient or Axl-deficient HCC cells was used to identify Gas6/Axl targets. Gain- and loss-of-function studies as well as proteomics were employed to characterize the role of PRAME (preferentially expressed antigen in melanoma). Expression of Axl/PRAME was assessed in publicly available HCC patient datasets and in 133 HCC cases. (3) Results: Exploitation of well-characterized HCC models expressing Axl or devoid of Axl allowed the identification of target genes including PRAME. Intervention with Axl signaling or MAPK/ERK1/2 resulted in reduced PRAME expression. PRAME levels were associated with a mesenchymal-like phenotype augmenting 2D cell migration and 3D cell invasion. Interactions with pro-oncogenic proteins such as CCAR1 suggested further tumor-promoting functions of PRAME in HCC. Moreover, PRAME showed elevated expression in Axl-stratified HCC patients, which correlates with vascular invasion and lowered patient survival. (4) Conclusions: PRAME is a bona fide target of Gas6/Axl/ERK signaling linked to EMT and cancer cell invasion in HCC. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
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14 pages, 1197 KiB  
Article
Renal Safety Profile of BCR-ABL Tyrosine Kinase Inhibitors in a Real-Life Setting: A Study Based on Vigibase®, the WHO Pharmacovigilance Database
by Morgane Cellier, Delphine Bourneau-Martin, Chadi Abbara, Alexandre Crosnier, Laurence Lagarce, Anne-Sophie Garnier and Marie Briet
Cancers 2023, 15(7), 2041; https://doi.org/10.3390/cancers15072041 - 29 Mar 2023
Cited by 5 | Viewed by 2002
Abstract
Background: Alongside their BCR-ABL specificity, TKIs used in chronic myeloid leukemia also target other tyrosine kinases expressed in the kidney such as PDGFR, c-KIT, SRC, and VEGFR, which may result in specific renal adverse drug reaction (ADR). To evaluate the renal safety profile [...] Read more.
Background: Alongside their BCR-ABL specificity, TKIs used in chronic myeloid leukemia also target other tyrosine kinases expressed in the kidney such as PDGFR, c-KIT, SRC, and VEGFR, which may result in specific renal adverse drug reaction (ADR). To evaluate the renal safety profile in real-life conditions, a case/non-case study was performed on VigiBase®, the WHO global safety database. Methods: From 7 November 2001 to 2 June 2021, all cases in which the involvement of imatinib, dasatinib, nilotinib, bosutinib, and ponatinib was suspected in the occurrence of renal ADR were extracted from VigiBase®. Disproportionality analyses were assessed using the reporting odds ratio. Results: A total of 1409 cases were included. Imatinib accounts for half of the reported cases. A signal of disproportionate reporting (SDR) of renal failure and fluid retention was found for the five TKIs. Only dasatinib and nilotinib were related to an SDR for nephrotic syndrome. Nilotinib and ponatinib were related to an SDR for renal artery stenosis, while dasatinib was related to an SDR for thrombotic microangiopathy. No SDR for tubulointerstitial nephritis was observed. Conclusion: This study identified a new safety signal, nephrotic syndrome, for nilotinib and highlights the importance of post-marketing safety surveillance. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
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13 pages, 4492 KiB  
Article
MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor
by Simona Gallo, Annapia Vitacolonna, Paolo Comoglio and Tiziana Crepaldi
Cancers 2022, 14(18), 4408; https://doi.org/10.3390/cancers14184408 - 11 Sep 2022
Cited by 4 | Viewed by 1970
Abstract
The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel involved in excitatory synaptic transmission. Outside the nervous system, the NMDAR is expressed in a variety of tissues and in cancers, notably in the highly invasive and metastatic triple-negative breast carcinoma. MET encodes the [...] Read more.
The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel involved in excitatory synaptic transmission. Outside the nervous system, the NMDAR is expressed in a variety of tissues and in cancers, notably in the highly invasive and metastatic triple-negative breast carcinoma. MET encodes the tyrosine kinase receptor for HGF and is a master regulator gene for “invasive growth”. In silico analysis shows that high expression of the NMDAR2B subunit is a negative prognostic factor in human invasive breast carcinoma. Here, we show that in triple-negative breast cancer cell lines NMDAR2B and MET proteins are coexpressed. HGF stimulation of these cells is followed by autophosphorylation of the MET kinase and phosphorylation of the NMDAR2B subunit at tyrosines 1252 and 1474. MET and phosphorylated NMDAR2B are physically associated, as demonstrated by co-immunoprecipitation, confocal immunofluorescence, and proximity ligation assays. Notably, pharmacological inhibition of NMDAR by MK801 and ifenprodil blunts the biological response to HGF. These results demonstrate the existence of a MET-NMDAR crosstalk driving the invasive program, paving the way for a new combinatorial therapy. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
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Review

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23 pages, 1690 KiB  
Review
Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators
by Ilaria Marrocco and Yosef Yarden
Cancers 2023, 15(20), 5009; https://doi.org/10.3390/cancers15205009 - 16 Oct 2023
Cited by 5 | Viewed by 3293
Abstract
Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only [...] Read more.
Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR+ lung cancer. Full article
(This article belongs to the Special Issue Growth Factors and Receptor Tyrosine Kinases in Development, Regeneration, and Tumorigenesis)
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