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Cited by 32Cancer, Hypoxia, and MetabolismHepatocellular Carcinoma Treatment and PrognosisAngiogenesis and VEGF in Cancer

The DOI matches its Crossref record; 441 of the 460 references it cites were found in a registry or an index.

Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment

Open access
Lappano, Rosamaria, Todd, Lauren A., Stanic, Mia, Cai, Qi, Maggiolini, Marcello, Marincola, Francesco, Pietrobon, Violena·2022·Cancers
DOI 10.3390/cancers14030539PMC PMC8833523
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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 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.

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Crossref · 10.3390/cancers14030539

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Figure 1 Schematic of tumor growth and progression (affected by hormone and GF signaling): somatic mutation, clonal expansion, intraluminal cell proliferation and intraluminal lesion formation, invasion, dissemination, the formation of micrometastases, resistant tumor clones, angiogenesis, and ultimately metastases.
Figure 1 Schematic of tumor growth and progression (affected by hormone and GF signaling): somatic mutation, clonal expansion, intraluminal cell proliferation and intraluminal lesion formation, invasion, dissemination, the formation of micrometastases, resistant tumor clones, angiogenesis, and ultimately metastases.CC BY · PubMed Central
Figure 2 In physioxia (right), hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF proteins by post-translational hydroxylation of two conserved prolyl residues in its α-subunit in an oxygen-dependent manner. Hydroxylation of HIF creates a binding site for pVHL that directs the polyubiquitylation of HIF-1α and its proteasomal degradation. In hypoxic conditions (left), HIF-1α binds to HIF-1β to form a heterodimer that acts as transcription factor, upregulating a variety of genes.
Figure 2 In physioxia (right), hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF proteins by post-translational hydroxylation of two conserved prolyl residues in its α-subunit in an oxygen-dependent manner. Hydroxylation of HIF creates a binding site for pVHL that directs the polyubiquitylation of HIF-1α and its proteasomal degradation. In hypoxic conditions (left), HIF-1α binds to HIF-1β to form a heterodimer that acts as transcription factor, upregulating a variety of genes.CC BY · PubMed Central
Figure 3 (A) Schematic of HypoxiCAR T-cell activation: A hypoxia-inducible CAR construct, whose transcription is mediated by HIF-1. (↑ means increase, ↓ means decrease) (B) HypoxiCAR T-cells are not excluded from HIF-1-stabilized regions of the tumor. Immunofluorescence images from a human oral tongue carcinoma. Nuclei are stained with DAPI (blue), anti-CD3 antibody (green), and anti-HIF-1α antibody (red); white denotes CD3 and HIF-1α co-localization. Scale bar 100 μm. (Reprinted with permission from Elsevier. Copyright (2021) Cell Reports Medicine [426]).
Figure 3 (A) Schematic of HypoxiCAR T-cell activation: A hypoxia-inducible CAR construct, whose transcription is mediated by HIF-1. (↑ means increase, ↓ means decrease) (B) HypoxiCAR T-cells are not excluded from HIF-1-stabilized regions of the tumor. Immunofluorescence images from a human oral tongue carcinoma. Nuclei are stained with DAPI (blue), anti-CD3 antibody (green), and anti-HIF-1α antibody (red); white denotes CD3 and HIF-1α co-localization. Scale bar 100 μm. (Reprinted with permission from Elsevier. Copyright (2021) Cell Reports Medicine [426]).CC BY · PubMed Central

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Metadata

Authors
Lappano, R., Todd, L. A., Stanic, M., Cai, Q., Maggiolini, M., Marincola, F., & Pietrobon, V.
Affiliations
  • University of Calabria (IT)
  • University of Waterloo (CA)
  • Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
  • Kite Pharma (United States) (US)
Corresponding author
  • Lappano, Rosamaria
  • Pietrobon, Violena
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-01-21
Volume
14
Issue
3
Pages
539
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers14030539
PMC
PMC8833523
OpenAlex
W4207059954
Cited by
32
References
460
Citations by year
2026: 8 · 2025: 11 · 2024: 5 · 2023: 5 · 2022: 3
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
Funders
Italian Association for Cancer Research (IG 21322)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
tumor microenvironment, hormones, growth factors, hypoxia, hypoxia-inducible factor, HIF signaling, tumor progression, tumor heterogeneity, metastasis, cancer immunotherapy, immune-excluded phenotype, adoptive immunotherapy, treatment resistance

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