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

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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 July 2021) | Viewed by 59277

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Prof. Dr. Anica Dricu

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Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 710204 Craiova, Romania
Interests: molecular targeted cancer therapy; cancer immunotherapy; biomarkers; stem cells; brain tumors
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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

Published Papers (11 papers)

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Editorial

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3 pages, 185 KiB

Open AccessEditorial

Oncogenic Signalling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities

by Anica Dricu

Int. J. Mol. Sci. 2022, 23(13), 7376; https://doi.org/10.3390/ijms23137376 - 2 Jul 2022

Cited by 2 | Viewed by 1086

Abstract

Cancer is a common name for several distinct diseases caused by uncontrolled cell growth and proliferation [...] Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

Research

Jump to: Editorial, Review

16 pages, 2048 KiB

Open AccessArticle

IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses

by Taylor A. Harper, Silvia M. Bacot, Christie Jane Fennell, Rebecca L. Matthews, Christina Zhu, Peng Yue, Alexander Benton, Devira Friedman, Adovi Akue, Mark A. KuKuruga, Shiowjen Lee, Tao Wang and Gerald M. Feldman

Int. J. Mol. Sci. 2021, 22(21), 11848; https://doi.org/10.3390/ijms222111848 - 31 Oct 2021

Cited by 4 | Viewed by 2548

Abstract

Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far demonstrated limited efficacy for most patients, and it remains unclear why this is so. Interleukin 10 (IL-10) is a cytokine that has been recognized as a central player in cancer biology with its ability to inhibit anti-tumor T cell responses. Recent studies suggest that IL-10 might also exert some intrinsic anti-tumor T cell responses, and clinical studies using recombinant IL-10 alone or in combination with ICI are underway. This paradoxical effect of IL-10 and its underlying mechanisms impacting ICI-modulated T cell responses remain poorly understood. In this study, using an in vitro mixed lymphocyte reaction assay, we found that treatment with ICIs such as the anti-programmed cell death receptor-1 (PD-1) mAb nivolumab elicits a strong expression of IL-10. While neutralization of IL-10 signaling with an anti-IL-10 specific mAb significantly decreases the production of IFN-γ by T cells in a cohort of donor cells, the opposite effect was observed in other donor cells. Similarly, neutralization of IL-10 signaling significantly decreases the expression of T cell activation markers Ki67 and CD25, as well as the production of Granzyme B in a cohort of donor cells, whereas the opposite effect was observed in others. Furthermore, we found that nivolumab and IL-10 differentially modulate the signal transducer and activator of transcription 3 (STAT3) and AKT serine–threonine kinase pathways. Finally, we found that nivolumab activates the mitogen-activated protein kinase (MAPK) pathway, which in turn is responsible for the observed induction of IL-10 production by nivolumab. These findings provide new insights into the mechanisms underlying anti-PD-1-modulated T cell responses by IL-10, which could lead to the discovery of novel combination treatments that target IL-10 and immune checkpoint molecules. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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14 pages, 3428 KiB

Open AccessArticle

Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma

by Alina Maria Mehedințeanu, Veronica Sfredel, Puiu Olivian Stovicek, Michael Schenker, Georgică Costinel Târtea, Octavian Istrătoaie, Ana-Maria Ciurea and Cristin Constantin Vere

Int. J. Mol. Sci. 2021, 22(4), 2042; https://doi.org/10.3390/ijms22042042 - 18 Feb 2021

Cited by 6 | Viewed by 2680

Abstract

The aim of our study was to assess the sympathetic nervous system’s involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system’s activity predicts increased gastric carcinoma severity. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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16 pages, 3827 KiB

Open AccessArticle

SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells

by Robert Jenke, Miriam Holzhäuser-Rein, Stefanie Mueller-Wilke, Florian Lordick, Achim Aigner and Thomas Büch

Int. J. Mol. Sci. 2021, 22(1), 82; https://doi.org/10.3390/ijms22010082 - 23 Dec 2020

Cited by 3 | Viewed by 2214

Abstract

MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro, whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of other oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this study, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in this respect. This also included the chromatin-organizer protein SATB1, as an established regulator of HER expression in other tumor entities. In a panel of MET-amplified gastric carcinoma cell lines, cell growth under anchorage-dependent and independent conditions was studied upon inhibitor treatment or siRNA-mediated knockdown. Expression analyses were performed using RT-qPCR, FACS, and immunoblots. Signal transduction was monitored via antibody arrays and immunoblots. As expected, MET inhibition led to a growth arrest and inhibition of MAPK signaling. Strikingly, however, this was accompanied by a rapid and profound upregulation of the oncogenic receptor HER3. This finding was determined as functionally relevant, since HER3 activation by HRG led to partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced upon HRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3 upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogating the HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combined HER3/MET inhibition as strategy to overcome resistance towards MET inhibitors. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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Review

Jump to: Editorial, Research

23 pages, 2997 KiB

Open AccessReview

Transcriptomic Crosstalk between Gliomas and Telencephalic Neural Stem and Progenitor Cells for Defining Heterogeneity and Targeted Signaling Pathways

by Roxana Deleanu, Laura Cristina Ceafalan and Anica Dricu

Int. J. Mol. Sci. 2021, 22(24), 13211; https://doi.org/10.3390/ijms222413211 - 8 Dec 2021

Cited by 3 | Viewed by 2488

Abstract

Recent studies have begun to reveal surprising levels of cell diversity in the human brain, both in adults and during development. Distinctive cellular phenotypes point to complex molecular profiles, cellular hierarchies and signaling pathways in neural stem cells, progenitor cells, neuronal and glial cells. Several recent reports have suggested that neural stem and progenitor cell types found in the developing and adult brain share several properties and phenotypes with cells from brain primary tumors, such as gliomas. This transcriptomic crosstalk may help us to better understand the cell hierarchies and signaling pathways in both gliomas and the normal brain, and, by clarifying the phenotypes of cells at the origin of the tumor, to therapeutically address their most relevant signaling pathways. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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24 pages, 1091 KiB

Open AccessReview

Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?

by Constantin Stefani, Daniela Miricescu, Iulia-Ioana Stanescu-Spinu, Remus Iulian Nica, Maria Greabu, Alexandra Ripszky Totan and Mariana Jinga

Int. J. Mol. Sci. 2021, 22(19), 10260; https://doi.org/10.3390/ijms221910260 - 23 Sep 2021

Cited by 113 | Viewed by 8999

Abstract

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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15 pages, 1834 KiB

Open AccessReview

ELTD1—An Emerging Silent Actor in Cancer Drama Play

by Ani-Simona Sevastre, Iuliana M. Buzatu, Carina Baloi, Alexandru Oprita, Alexandra Dragoi, Ligia G. Tataranu, Oana Alexandru, Stefania Tudorache and Anica Dricu

Int. J. Mol. Sci. 2021, 22(10), 5151; https://doi.org/10.3390/ijms22105151 - 13 May 2021

Cited by 9 | Viewed by 2197

Abstract

The epidermal growth factor, latrophilin, and seven transmembrane domain–containing protein 1 (ELTD1), is a member of the G–protein coupled receptors (GPCRs) superfamily. Although discovered in 2001, ELTD1 has been investigated only by a few research groups, and important data about its role in normal and tumor cells is still missing. Even though its functions and structure are not yet fully understood, recent studies show that ELTD1 has a role in both physiological and pathological angiogenesis, and it appears to be a very important biomarker and a molecular target in cancer diseases. Upregulation of ELTD1 in malignant cells has been reported, and correlated with poor cancer prognosis. This review article aims to compile the existing data and to discuss the current knowledge on ELTD1 structure and signaling, and its role in physiological and neoplastic conditions. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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12 pages, 419 KiB

Open AccessReview

The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer

by Oana-Stefana Purcaru, Stefan-Alexandru Artene, Edmond Barcan, Cristian Adrian Silosi, Ilona Stanciu, Suzana Danoiu, Stefania Tudorache, Ligia Gabriela Tataranu and Anica Dricu

Int. J. Mol. Sci. 2021, 22(9), 4830; https://doi.org/10.3390/ijms22094830 - 2 May 2021

Cited by 17 | Viewed by 3049

Abstract

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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20 pages, 1241 KiB

Open AccessReview

Updated Insights on EGFR Signaling Pathways in Glioma

by Alexandru Oprita, Stefania-Carina Baloi, Georgiana-Adeline Staicu, Oana Alexandru, Daniela Elise Tache, Suzana Danoiu, Elena Simona Micu and Ani-Simona Sevastre

Int. J. Mol. Sci. 2021, 22(2), 587; https://doi.org/10.3390/ijms22020587 - 8 Jan 2021

Cited by 75 | Viewed by 12581

Abstract

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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24 pages, 789 KiB

Open AccessReview

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

by Daniela Miricescu, Alexandra Totan, Iulia-Ioana Stanescu-Spinu, Silviu Constantin Badoiu, Constantin Stefani and Maria Greabu

Int. J. Mol. Sci. 2021, 22(1), 173; https://doi.org/10.3390/ijms22010173 - 26 Dec 2020

Cited by 315 | Viewed by 17287

Abstract

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20–30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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19 pages, 1218 KiB

Open AccessReview

Autophagy—A Hidden but Important Actor on Oral Cancer Scene

by Totan Alexandra, Imre Melescanu Marina, Miricescu Daniela, Stanescu Iulia Ioana, BencZe Maria, Radulescu Radu, Tancu Ana Maria, Spinu Tudor and Greabu Maria

Int. J. Mol. Sci. 2020, 21(23), 9325; https://doi.org/10.3390/ijms21239325 - 7 Dec 2020

Cited by 16 | Viewed by 2923

Abstract

The duration of denture use, oral hygiene, smoking and male sex were identified as risk factors for oral mucosal lesions. As it is well known, all the oral mucosal lesions associated with risk factors have an important degree of malignity. Chronic mechanical irritation can be another cause of oral cancer and it is produced by the constant action of a deleterious agent from the oral cavity. Autophagy represents a complex evolutionary conserved catabolic process in which cells self-digest intracellular organelles in order to regulate their normal turnover and remove the damaged ones with compromised function to further maintain homeostasis. Autophagy is modulated by mTOR kinase and indirectly by PI3K/AKT survival pathway. Due to its dual capacity to either induce cell death or promote cell survival, important evidence pointed that autophagy has a two-faced role in response to chemotherapy in cancer. In conclusion, understanding how to overcome cytoprotective autophagy and how to take advantage of autophagic cell death is critical in order to enhance the cancer cells sensitivity to particular therapeutic agents. Full article

(This article belongs to the Special Issue Oncogenic Signaling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities)

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