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Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms...
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Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 20749

Special Issue Editor

Prof. Dr. Anica Dricu

E-Mail Website
Guest Editor
Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
Interests: molecular targeted cancer therapy; cancer immunotherapy; biomarkers; stem cells; brain tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

At the molecular level, the activation of growth factor receptors (GFRs) induces a mitogenic response and maintains cancer cell growth. The majority of malignant diseases are related to aberrant intra- and intercellular communication, associated with the GFR-mediated pathways. Moreover, the evasion of apoptotic signals and the requirement of angiogenesis were also found to be of fundamental importance for tumor progression and metastasis. In this context, high expression of GFRs aids blood vessel formation, cell migration, and the inhibition of apoptosis. GFR-directed therapy that would theoretically selectively kill malignant cells and reduce the toxicity associated with nonselective conventional chemotherapy may be a promising treatment for cancer. Based on this rationale, different strategies have been developed to inhibit the oncogenic effects of GFRs (e.g., small-molecule inhibitors, monoclonal antibodies, siRNA, antisense oligodeoxynucleotides, triple helix, dominant-negative mutants, etc.).

Many intracellular proteins involved in GFRs signal transduction can also function as oncogenes. Mutations affecting key proteins in RAS/MAPK and PI3K/AKT pathways are known to be crucial in maintaining the malignancy of different types of cancers. This information has guided the development of compounds designed to target one or more of these pathways in cancer cells.

Even though there have been important advances in our understanding of GFRs and their signaling, certain essential information is still lacking, and these membrane receptors are still being laboriously studied by several research groups, to find therapeutic solutions to unmet medical needs.

This Special Issue will cover the latest preclinical and clinical progress made in the areas associated with GFRs’ oncogenic signaling.

Prof. Dr. Anica Dricu
Guest Editor

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Keywords

  • growth factor receptors
  • signal transduction
  • malignant diseases
  • apoptosis
  • angiogenesis
  • molecular therapy
  • tyrosine kinases

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Published Papers (5 papers)

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Research

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13 pages, 1678 KiB  
Communication
Immunohistochemistry Screening of Different Tyrosine Kinase Receptors in Canine Solid Tumors—Part I: Proposal of a Receptor Panel to Predict Therapies
by Denner Santos Dos Anjos, Patrick Antônio Sonaglio Civa, Juliana Werner, Igor Simões Tiagua Vicente and Carlos Eduardo Fonseca-Alves
Int. J. Mol. Sci. 2024, 25(15), 8438; https://doi.org/10.3390/ijms25158438 - 2 Aug 2024
Cited by 1 | Viewed by 1756
Abstract
The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. [...] Read more.
The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. Therefore, this study aimed to screen different tumor subtypes regarding TKI target immunoexpression as a predictor strategy to personalize the canine cancer treatment. It included 18 prostatic carcinomas, 36 soft tissue sarcomas, 20 mammary gland tumors, 6 urothelial bladder carcinomas, and 7 tumors from the endocrine system. A total of 87 patients with paraffin blocks were used to perform immunohistochemistry (IHC) of human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptors 1 (EGFR1), vascular endothelial growth factor receptor 2 (VEGFR-2), platelet derived growth factor receptor beta (PDGFR-β), c-KIT, and extracellular signal-regulated kinase 1/2 (ERK1/ERK2). The immunohistochemical screening revealed a heterogeneous protein expression among histological types with mesenchymal tumors showing the lowest expression level and carcinomas the highest expression. We have demonstrated by IHC screening that HER2, EGFR1, VEGFR-2, PDGFR-β and ERK1/ERK2 are commonly overexpressed in dogs with different carcinomas, and KIT expression is considered relatively low in the analyzed samples. Full article
(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities)
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14 pages, 4592 KiB  
Article
The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor
by Dogus Murat Altintas, Simona Gallo, Cristina Basilico, Marina Cerqua, Alessio Bocedi, Annapia Vitacolonna, Orsola Botti, Elena Casanova, Ilaria Rancati, Chiara Milanese, Sara Notari, Giorgia Gambardella, Giorgio Ricci, Pier Giorgio Mastroberardino, Carla Boccaccio, Tiziana Crepaldi and Paolo Maria Comoglio
Int. J. Mol. Sci. 2022, 23(20), 12427; https://doi.org/10.3390/ijms232012427 - 17 Oct 2022
Cited by 7 | Viewed by 2514
Abstract
The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases [...] Read more.
The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand—hepatocyte growth factor (HGF)—such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein. Full article
(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities)
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17 pages, 4531 KiB  
Article
Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
by Fang Hua, Wenzhuo Hao, Lingyan Wang and Shitao Li
Int. J. Mol. Sci. 2021, 22(21), 11875; https://doi.org/10.3390/ijms222111875 - 2 Nov 2021
Cited by 19 | Viewed by 3786
Abstract
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with [...] Read more.
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy. Full article
(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities)
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Review

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24 pages, 1974 KiB  
Review
An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma
by Silvia Mara Baez Rodriguez, Amira Kamel, Gheorghe Vasile Ciubotaru, Gelu Onose, Ani-Simona Sevastre, Veronica Sfredel, Suzana Danoiu, Anica Dricu and Ligia Gabriela Tataranu
Int. J. Mol. Sci. 2023, 24(13), 11110; https://doi.org/10.3390/ijms241311110 - 5 Jul 2023
Cited by 40 | Viewed by 5384
Abstract
Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied [...] Read more.
Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood–brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents. Full article
(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities)
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18 pages, 1303 KiB  
Review
Fatty Acids, CD36, Thrombospondin-1, and CD47 in Glioblastoma: Together and/or Separately?
by Cristiana Tanase, Ana Maria Enciu, Elena Codrici, Ionela Daniela Popescu, Maria Dudau, Ana Maria Dobri, Sevinci Pop, Simona Mihai, Ancuța-Augustina Gheorghișan-Gălățeanu and Mihail Eugen Hinescu
Int. J. Mol. Sci. 2022, 23(2), 604; https://doi.org/10.3390/ijms23020604 - 6 Jan 2022
Cited by 26 | Viewed by 6450
Abstract
Glioblastoma (GBM) is one of the most aggressive tumors of the central nervous system, characterized by a wide range of inter- and intratumor heterogeneity. Accumulation of fatty acids (FA) metabolites was associated with a low survival rate in high-grade glioma patients. The diversity [...] Read more.
Glioblastoma (GBM) is one of the most aggressive tumors of the central nervous system, characterized by a wide range of inter- and intratumor heterogeneity. Accumulation of fatty acids (FA) metabolites was associated with a low survival rate in high-grade glioma patients. The diversity of brain lipids, especially polyunsaturated fatty acids (PUFAs), is greater than in all other organs and several classes of proteins, such as FA transport proteins (FATPs), and FA translocases are considered principal candidates for PUFAs transport through BBB and delivery of PUFAs to brain cells. Among these, the CD36 FA translocase promotes long-chain FA uptake as well as oxidated lipoproteins. Moreover, CD36 binds and recognizes thrombospondin-1 (TSP-1), an extracellular matrix protein that was shown to play a multifaceted role in cancer as part of the tumor microenvironment. Effects on tumor cells are mediated by TSP-1 through the interaction with CD36 as well as CD47, a member of the immunoglobulin superfamily. TSP-1/CD47 interactions have an important role in the modulation of glioma cell invasion and angiogenesis in GBM. Separately, FA, the two membrane receptors CD36, CD47, and their joint ligand TSP-1 all play a part in GBM pathogenesis. The last research has put in light their interconnection/interrelationship in order to exert a cumulative effect in the modulation of the GBM molecular network. Full article
(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer 2.0: Mechanisms and Therapeutic Opportunities)
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