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Cancers
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Growth Factors as Master Regulators of Cancer Progression
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Growth Factors as Master Regulators of Cancer Progression

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

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 17662

Special Issue Editor

Dr. Rosalba D’Alessandro

E-Mail Website
Guest Editor
Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, Via Turi 27, 70013 Castellana Grotte, BA, Italy
Interests: HCC; gastric cancer; target therapy; drug resistance; combined therapy; synergism; chemotherapeutic agents; growth factors; angiogenesis; cell cultures; proliferation; apoptosis; migration; signaling; PI3K/Akt; MAPK
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Progression through the cell cycle is finely regulated by several growth factors that engage intracellular signaling pathways controlling tissue homeostasis. All these events are profoundly subverted by cancer. In particular, the oncogenic mechanisms, active during tumorigenesis at crucial steps in mitogen signaling, seem to replace the mechanisms of specific growth factors. Growth factors can be considered potential master regulators in all the phases of tumor progression from clonal expansion to invasion across natural tissue barriers, angiogenesis and metastasis.

Recent insights suggest that cancer cells functionally model their surrounding microenvironment to support tumor growth and dissemination through multiple strategies, including growth factors release, alterations of extracellular matrix and cell to cell interactions. Cancer cell-secreted growth factors can further stimulate cell growth via autocrine mechanisms. Reciprocally, tumor microenvironment, with its complex repertoire of multiple cells, inflammatory cytokines and associated growth factors, profoundly influences cancer cell metabolism to provide selective advantage during tumorigenesis. Paracrine actions of growth factors and cytokines, involving myeloid, mesenchymal, and endothelial cells, may also influence the stepwise series of events that lead to malignancy.

Detailed knowledge of the relationships between tumor, immune cells and tumor microenvironment, is providing new criteria for patient stratification, opening the way to more personalized therapies aimed to overcome resistance phenomena. In this scenario, new strategies in cancer therapy are being developed interfering at various steps of growth factor signaling pathways and/or combining target therapy to standard chemotherapy or immunotherapy.

Through the development of both new research articles and timely reviews, this Special Issue aims to provide the framework of growth factors that makes these molecules “the main mediators of cancer growth and progression”.

Dr. Rosalba D’Alessandro
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 short 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

  • carcinogenesis
  • Oncogenes
  • cancer progression
  • Growth factors
  • Microenvironment
  • Autocrine mechanisms
  • Paracrine mechanisms
  • Resistance
  • Personalized therapies
  • Target therapies
  • Combined therapies

Published Papers (5 papers)

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Research

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17 pages, 3045 KiB  
Article
RAC1B Regulation of TGFB1 Reveals an Unexpected Role of Autocrine TGFβ1 in the Suppression of Cell Motility
by Hendrik Ungefroren, Hannah Otterbein, Ulrich F. Wellner, Tobias Keck, Hendrik Lehnert and Jens-Uwe Marquardt
Cancers 2020, 12(12), 3570; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123570 - 29 Nov 2020
Cited by 10 | Viewed by 2489
Abstract
Autocrine transforming growth factor (TGF)β has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous TGFB1 [...] Read more.
Autocrine transforming growth factor (TGF)β has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous TGFB1 remain poorly characterized. In both cancer types, the small GTPase RAC1B inhibits cell motility induced by recombinant human TGFβ1 via downregulation of the TGFβ type I receptor, ALK5, but whether RAC1B also impacts autocrine TGFβ signaling has not yet been studied. Intriguingly, RNA interference-mediated knockdown (RNAi-KD) or CRISPR/Cas-mediated knockout of RAC1B in TGFβ1-secreting PDAC-derived Panc1 cells resulted in a dramatic decrease in secreted bioactive TGFβ1 in the culture supernatants and TGFB1 mRNA expression, while the reverse was true for TNBC-derived MDA-MB-231 cells ectopically expressing RAC1B. Surprisingly, the antibody-mediated neutralization of secreted bioactive TGFβ or RNAi-KD of the endogenous TGFB1 gene, was associated with increased rather than decreased migratory activities of Panc1 and MDA-MB-231 cells, upregulation of the promigratory genes SNAI1, SNAI2 and RAC1, and downregulation of the invasion suppressor genes CDH1 (encoding E-cadherin) and SMAD3. Intriguingly, ectopic re-expression of SMAD3 was able to rescue Panc1 and MDA-MB-231 cells from the TGFB1 KD-induced rise in migratory activity. Together, these data suggest that RAC1B favors synthesis and secretion of autocrine TGFβ1 which in a SMAD3-dependent manner blocks EMT-associated gene expression and cell motility. Full article
(This article belongs to the Special Issue Growth Factors as Master Regulators of Cancer Progression)
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Review

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16 pages, 1021 KiB  
Review
Another One Bites the Gut: Nuclear Receptor LRH-1 in Intestinal Regeneration and Cancer
by Roberta Zerlotin, Maria Arconzo, Elena Piccinin and Antonio Moschetta
Cancers 2021, 13(4), 896; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040896 - 20 Feb 2021
Cited by 3 | Viewed by 2596
Abstract
The process of self-renewal in normal intestinal epithelium is characterized by a fine balance between proliferation, differentiation, migration, and cell death. When even one of these aspects escapes the normal control, cellular proliferation and differentiation are impaired, with consequent onset of tumorigenesis. In [...] Read more.
The process of self-renewal in normal intestinal epithelium is characterized by a fine balance between proliferation, differentiation, migration, and cell death. When even one of these aspects escapes the normal control, cellular proliferation and differentiation are impaired, with consequent onset of tumorigenesis. In humans, colorectal cancer (CRC) is the main pathological manifestation of this derangement. Nowadays, CRC is the world’s fourth most deadly cancer with a limited survival after treatment. Several conditions can predispose to CRC development, including dietary habits and pre-existing inflammatory bowel diseases. Given their extraordinary ability to interact with DNA, it is widely known that nuclear receptors play a key role in the regulation of intestinal epithelium, orchestrating the expression of a series of genes involved in developmental and homeostatic pathways. In particular, the nuclear receptor Liver Receptor Homolog-1 (LRH-1), highly expressed in the stem cells localized in the crypts, promotes intestine cell proliferation and renewal in both direct and indirect DNA-binding manner. Furthermore, LRH-1 is extensively correlated with diverse intestinal inflammatory pathways. These evidence shed a light in the dynamic intestinal microenvironment in which increased regenerative epithelial cell turnover, mutagenic insults, and chronic DNA damages triggered by factors within an inflammatory cell-rich microenvironment act synergistically to favor cancer onset and progression. Full article
(This article belongs to the Special Issue Growth Factors as Master Regulators of Cancer Progression)
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18 pages, 1737 KiB  
Review
Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma
by Stefanie de Groot, Bas Röttgering, Hans Gelderblom, Hanno Pijl, Karoly Szuhai and Judith R. Kroep
Cancers 2020, 12(12), 3568; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123568 - 29 Nov 2020
Cited by 12 | Viewed by 2831
Abstract
Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several [...] Read more.
Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor. Full article
(This article belongs to the Special Issue Growth Factors as Master Regulators of Cancer Progression)
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20 pages, 757 KiB  
Review
The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives
by Maria Francesca Santolla and Marcello Maggiolini
Cancers 2020, 12(10), 3029; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103029 - 18 Oct 2020
Cited by 51 | Viewed by 6549
Abstract
One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several [...] Read more.
One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer. Full article
(This article belongs to the Special Issue Growth Factors as Master Regulators of Cancer Progression)
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15 pages, 620 KiB  
Review
Colorectal Cancer and Bone Tissue: Fantastic Relations and Where to Find Them
by Isabella Gigante, Valeria Tutino, Valentina De Nunzio and Maria Notarnicola
Cancers 2020, 12(8), 2029; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082029 - 24 Jul 2020
Cited by 4 | Viewed by 2526
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. There is a need for the early diagnosis of CRC for a better prognostic outcome. It is, therefore, crucial to understand the CRC pathogenesis in all its aspects. In many cases, one of [...] Read more.
Colorectal cancer (CRC) is the third most common cancer worldwide. There is a need for the early diagnosis of CRC for a better prognostic outcome. It is, therefore, crucial to understand the CRC pathogenesis in all its aspects. In many cases, one of the main causes of cancer-related deaths is the presence of metastases. In this context, an often overlooked aspect is the metastatic tropism, since CRC, like other cancers, is more prone to metastasize some organs rather than others. Beyond the liver and lung, and differently from other types of cancers, a not usual site of CRC metastases is the bone. However, it may assume a crucial role in the development and the outcome of the disease. Therefore, this review aims to discuss the complex relations between bone markers and CRC pathogenesis, suggesting the use of these molecules as potential targets for therapeutic purposes. Different osteogenic molecules, some of whom are growth factors and are implicated in the different osteogenic pathways, have been proved to also be involved in CRC progression. Some of them are oncogenes, while others oncosuppressors, and in a future perspective, some of them may represent new potential CRC biomarkers. Full article
(This article belongs to the Special Issue Growth Factors as Master Regulators of Cancer Progression)
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