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

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.

Keywords: cancer; growth factors; hormones; hypoxia; hypoxia-inducible factors; immune exclusion; immunotherapies.

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 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 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]).