Travelling under pressure - hypoxia and shear stress in the metastatic journey

Abstract

Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant tissues. Circulating tumor cells (CTCs) represent a highly selected subpopulation of cancer cells that tamed these critical steps, and a better understanding of their biology and driving molecular principles may facilitate the development of novel tools to prevent metastasis. Here, we describe key research advances in this field, aiming at describing early metastasis-related processes such as collective invasion, shedding, and survival of CTCs in the bloodstream, paying particular attention to microenvironmental factors like hypoxia and mechanical stress, considered as important influencers of the metastatic journey.

Keywords: Circulating tumor cell (CTC); Hypoxia; Hypoxia-inducible factors; Metastasis; Shear stress.

Fig. 1

(a) In solid tumors, HIF-α is stabilized under conditions of low O₂ due to reduced vascularization and the establishment of a hypoxic microenvironment. (b) Post-transcriptional regulation of HIF-α subunits. Under normoxic conditions, PHD enzymes utilize oxygen and 2-oxoglutarate as substrates to hydroxylate two proline residues in the HIF-α subunit. These hydroxylation events are required for VHL to bind, ubiquitinate, and target HIF-α for proteasomal degradation. Under hypoxia, hydroxylation is inhibited and HIF-α stabilized. HIF-α heterodimerizes with HIF-1β, interacts with the transcriptional coactivators p300 and CBP, and binds to HRE elements within regulatory regions of target genes. Illustrations were created with BioRender.

Fig. 2

Regulation of glucose and glutamine metabolism and pH by HIF-α. Blue circles indicate proteins encoded by HIF-α target genes. To compensate for the reduced flux of glucose to citrate, reductive glutamine metabolism generates cytosolic citrate for de novo lipid synthesis. α-KG, α-ketoglutarate; Glu, glutamate; OXPHOS, oxidative phosphorylation; NBC, Na⁺/HCO₃⁻ co-transporter; TCA, tricarboxylic acid

Fig. 3

Hypoxia and shear stress regulate dissemination of circulating tumor cells (CTCs). Cancer cells are in interaction with several types of immune cells and experience various biophysical forces both in the primary tumor microenvironment and in the circulation. Primary tumors have normoxic and hypoxic regions with constant interstitial flow, inducing biochemical and biophysical signaling changes in cancer cells. Cancer cells can intravasate as single cells, as a group of cells (homotypic clusters) or together with non-neoplastic cells (heterotypic clusters). When CTCs enter the bloodstream, they are subjected to different levels of fluid shear stress that can lead to cell rupture and apoptosis, and initiate rapid signaling changes. Due to mechanical shielding, CTC clusters are more resistant to shear stress than single cells. In contrast, single cells are more prone to cell membrane blebbing caused by mechanical forces. MDSC, myeloid-derived suppressor cell; CAF, cancer-associated fibroblast; NK, natural killer cell. Illustrations were created with BioRender.