Abstract
Simple SummaryHormones and growth factors impact many processes in the cell. Moreover, these molecules influence tumor growth, as does a lack of oxygen (hypoxia) that characterizes cancer progression. Proteins that are stabilized by low oxygen tension, known as hypoxia-inducible factors (HIFs), help tumor cells to adapt to their environment. Of note, hormones and growth factors regulate the activity of HIFs toward malignant aggressiveness, including the resistance to therapy. In this review, we summarize the current knowledge regarding the role of hormones and growth factors in cancer development with a particular focus on their interplay with hypoxia and HIFs and comment on how these factors influence the response to cancer immunotherapy.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.
Highlights
Hormones and growth factors (GFs) are essential to the regulation of crucial processes in healthy cells
Similar studies revealed that hypoxia-inducible factors (HIFs)-1α is induced upon the stretching of rat vascular smooth muscle cells [127], and HIF-1α and HIF-2α are induced in skeletal muscle microvascular endothelial cells upon stretching of rat muscles, suggesting that both HIF-1α and HIF-2α contribute to stretch-induced capillary growth under non-hypoxic conditions [128]
Hormones and GFs are emerging as key regulators of HIF signaling, with impacts on tumor growth, metastasis, and response to therapeutic agents
Summary
Hormones that affect the growth of tumor cells are usually lipid-soluble molecules that can pass directly through the cellular membrane and bind to intracellular proteins or nuclear receptors to mediate downstream signaling events and gene expression. Despite activating classical signaling cascades, GFs can indirectly or directly function as transcription factors, as well as induce the activity of transcription factors, like Signal Transducers and Activators of Transcription (STATs), or SMADs, and mediate gene expression [5,10,11,12,13] Both hormones and GFs mediate important cellular processes [14]. GH has been demonstrated to affect the tissuespecific expression of microRNAs, indicating a novel role for GH beyond its classical function in the activation of signaling pathways [13,16] Another example of GF binding that affects downstream cellular signaling pathways that underlie the development of prominent tumor signatures is the binding of IGF-I to its receptor in the PI3K/AKT pathway. The following section will describe how hormones and GFs influence the stages of tumor growth and progression
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