Lights and Shadows in the Communication between Hormones and Growth Factor Signaling in Cancer

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

Deadline for manuscript submissions: closed (30 December 2021) | Viewed by 17434

Special Issue Editors

Associate Professor, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy
Interests: hormones; hormone receptors; growth factors; RTKs; GPCRs; cancer microenvironment; CAFs; hypoxia; signal transduction; endocrine-related cancers
Special Issues, Collections and Topics in MDPI journals
Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Interests: IGF system; insulin receptor isoforms; endocrine-related cancers; thyroid cancer; steroid receptors; GPCRs; RTKs; RAGE; receptor crosstalk
Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Interests: IGF system; insulin receptor isoforms; endocrine-related cancers; thyroid cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has been well established that a variety of malignant tumors, such as cancers of the breast, endometrium, prostate, and testis, are responsive to sex steroids and that differentiated thyroid cancers are responsive to pituitary thyroid-stimulating hormone (TSH). Collectively, these tumors are referred to as endocrine related cancers. Anti-estrogenic/anti-androgenic treatments are commonly used to hamper sex steroid responsive cancers, while l-thyroxine therapy is used to suppress the growth effect of TSH in differentiated thyroid cancer. Moreover, other systemic hormones, such as insulin, pituitary growth hormone, prolactin, and IGF-1, have been involved in the progression of a variety of malignancies. Malignant tumors may present upregulation of hormone receptors as well as overactivation or biased activation of hormone downstream signaling.

Together with systemic hormones, the broad and heterogeneous class of molecules classified as growth factors represents an additional relevant set of signaling mediators which are produced locally and serve as space-restrained triggers of a number of cell and tissue functions.

Notwithstanding the ability to regulate relevant physiological processes, both hormone and growth factor receptors mediate oncogenic functions in several cancer histotypes and activate molecular programs involved in the regulation of a wide array of biological effects, including cell proliferation, migration, invasion, angiogenesis, and inflammation, as well as resistance to anticancer therapy. These actions are coordinated by a complex instruction of the transcriptional (mRNA and noncoding RNA) and epigenetic machinery, the modulation of protein expression and function, and the re-programming of cell metabolism.

Furthermore, both hormone and growth factor receptors are implicated in landscaping the tumor microenvironment by impacting the biology of numerous cellular components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), adipocytes, endothelial cells, and cancer stem cells (CSCs). Due to the multitude of cancer-promoting actions mediated, the pharmaceutical targeting of these receptors constitutes a valuable therapeutic option in the clinical management of cancer patients. Nevertheless, therapeutic strategies limited to the selective targeting of a single receptor may fail in getting the highest clinical benefit.

In this scenario, available evidence indicates that hormone and growth factor receptors cooperate in triggering transduction networks that facilitate the acquisition of aggressive features and therapy resistance in cancer. For instance, this bidirectional crosstalk may involve the ability of hormones and growth factors to reciprocally regulate the expression of cognate receptors, ligands, and transduction partners. Additionally, a physical interaction between different receptors may boost major intracellular signaling events and biological responses. The preferential use of alternate receptors others than classical cognate receptors may serve as an additional signaling route that facilitates the establishment of biased signaling in cancer cells.

Clearly, this intricate scenario presents multiple nodes of connections and deserves a better characterization of the underlying mechanisms for critical potential implications in a clinical setting. For instance, a better clarification of hormone and growth factor interaction in cancer may pave the way for the identification of lifestyle intervention that might be of benefit in controlling disease progression. Moreover, the design of compounds for the multitargeting of hormone and growth factor receptors represents a promising therapeutic approach which adds to the possible use of combination therapies.

This Special Issue aims at addressing open questions in the regulation and function of these receptors in cancer. A thorough scrutiny of the bidirectional crosstalk between hormone and growth factor receptors may help to cover essential gaps in the current knowledge of signaling cooperativity. Collecting the latest preclinical and clinical progresses made in this field could be beneficial with regard to better addressing unmet clinical needs in endocrine-related cancers.

Prof. Marcello Maggiolini
Dr. Rosamaria Lappano
Dr. Ernestina Marianna De Francesco
Prof. Antonino Belfiore
Guest Editors

Manuscript Submission Information

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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

  • hormones
  • hormone receptors
  • growth factors
  • RTKs
  • GPCRs
  • signal transduction
  • cancer microenvironment
  • endocrine-related cancers

Published Papers (5 papers)

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Research

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19 pages, 8085 KiB  
Article
Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells
by Danilo Ranieri, Luisa Guttieri, Salvatore Raffa, Maria Rosaria Torrisi and Francesca Belleudi
Cancers 2021, 13(19), 4993; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194993 - 05 Oct 2021
Cited by 4 | Viewed by 1544
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling are involved in epidermal carcinogenesis, the aim of this work has been to assess the contribution of these oncogenic events also in the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 in terms of intracellular signaling activation, upregulation of EMT-related transcription factors and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. Moreover, shut-off via specific protein depletion of PKCε signaling, activated by high expression of FGFR2c resulted in a reversion of EMT profile, as well as in a recovery of the autophagic process. The detailed biochemical analysis of the intracellular signaling indicated that PKCε, bypassing AKT and directly converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible effective therapeutic approach in counteracting aggressive phenotype in cancer. Full article
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19 pages, 4674 KiB  
Article
Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer
by Maria Grazia Muoio, Marianna Talia, Rosamaria Lappano, Andrew H. Sims, Veronica Vella, Francesca Cirillo, Livia Manzella, Marika Giuliano, Marcello Maggiolini, Antonino Belfiore and Ernestina Marianna De Francesco
Cancers 2021, 13(4), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040621 - 04 Feb 2021
Cited by 21 | Viewed by 4121
Abstract
Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin [...] Read more.
Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis. Full article
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19 pages, 5350 KiB  
Article
Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer
by Rosaria Benedetti, Chiara Papulino, Giulia Sgueglia, Ugo Chianese, Tommaso De Marchi, Francesco Iovino, Dante Rotili, Antonello Mai, Emma Niméus, Carmela Dell’ Aversana and Lucia Altucci
Cancers 2021, 13(3), 543; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030543 - 01 Feb 2021
Cited by 11 | Viewed by 2147
Abstract
The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, [...] Read more.
The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy. Full article
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36 pages, 1970 KiB  
Review
Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment
by Rosamaria Lappano, Lauren A. Todd, Mia Stanic, Qi Cai, Marcello Maggiolini, Francesco Marincola and Violena Pietrobon
Cancers 2022, 14(3), 539; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030539 - 21 Jan 2022
Cited by 8 | Viewed by 2971
Abstract
Hormones and growth factors (GFs) are signaling molecules implicated in the regulation of a variety of cellular processes. They play important roles in both healthy and tumor cells, where they function by binding to specific receptors on target cells and activating downstream signaling [...] Read more.
Hormones and growth factors (GFs) are signaling molecules implicated in the regulation of a variety of cellular processes. They play important roles in both healthy and tumor cells, where they function by binding to specific receptors on target cells and activating downstream signaling cascades. The stages of tumor progression are influenced by hormones and GF signaling. Hypoxia, a hallmark of cancer progression, contributes to tumor plasticity and heterogeneity. Most solid tumors contain a hypoxic core due to rapid cellular proliferation that outgrows the blood supply. In these circumstances, hypoxia-inducible factors (HIFs) play a central role in the adaptation of tumor cells to their new environment, dramatically reshaping their transcriptional profile. HIF signaling is modulated by a variety of factors including hormones and GFs, which activate signaling pathways that enhance tumor growth and metastatic potential and impair responses to therapy. In this review, we summarize the role of hormones and GFs during cancer onset and progression with a particular focus on hypoxia and the interplay with HIF proteins. We also discuss how hypoxia influences the efficacy of cancer immunotherapy, considering that a hypoxic environment may act as a determinant of the immune-excluded phenotype and a major hindrance to the success of adoptive cell therapies. Full article
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29 pages, 1712 KiB  
Review
Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression
by Damiano Cosimo Rigiracciolo, Francesca Cirillo, Marianna Talia, Lucia Muglia, Jorge Silvio Gutkind, Marcello Maggiolini and Rosamaria Lappano
Cancers 2021, 13(4), 645; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040645 - 05 Feb 2021
Cited by 27 | Viewed by 5507
Abstract
Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor [...] Read more.
Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors. Full article
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