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

SIMPLE SUMMARY: Hormones 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. 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.