Crosstalk between Hypoxia and Extracellular Matrix in the Tumor Microenvironment in Breast Cancer

Abstract

Even though breast cancer is the most diagnosed cancer among women, treatments are not always successful in preventing its progression. Recent studies suggest that hypoxia and the extracellular matrix (ECM) are important in altering cell metabolism and tumor metastasis. Therefore, the aim of this review is to study the crosstalk between hypoxia and the ECM and to assess their impact on breast cancer progression. The findings indicate that hypoxic signaling engages multiple mechanisms that directly contribute to ECM remodeling, ultimately increasing breast cancer aggressiveness. Second, hypoxia and the ECM cooperate to alter different aspects of cell metabolism. They mutually enhance aerobic glycolysis through upregulation of glucose transport, glycolytic enzymes, and by regulating intracellular pH. Both alter lipid and amino acid metabolism by stimulating lipid and amino acid uptake and synthesis, thereby providing the tumor with additional energy for growth and metastasis. Third, YAP/TAZ signaling is not merely regulated by the tumor microenvironment and cell metabolism, but it also regulates it primarily through its target c-Myc. Taken together, this review provides a better understanding of the crosstalk between hypoxia and the ECM in breast cancer. Additionally, it points to a role for the YAP/TAZ mechanotransduction pathway as an important link between hypoxia and the ECM in the tumor microenvironment, driving breast cancer progression.

Hypoxia-Induced Downregulation of miR-29 in Renal Tumor Cells Affects Collagen IV Subunit Expression through Multiple Sites

“…Hypoxia induces changes in the extracellular matrix of tumor cells [ 20 ], and collagen IV is an important component of the extracellular matrix [ 21 ]. In this study, we analyzed the sequencing results of renal cancer cells under hypoxia and found that the expression of miR-29b was changed.…”

Lipid Metabolism Heterogeneity and Crosstalk with Mitochondria Functions Drive Breast Cancer Progression and Drug Resistance

“…Under the hypoxic and metabolic stress conditions encountered during cancer development, there are multiple transcription factors and enzymes that are activated in cancer cells to cope with cell stress and the nutrient and energy needs for survival in a harsh TME. Hypoxic signaling involves several mechanisms that directly contribute to the deregulation of glycolysis, acidosis, lipid metabolism, ECM remodeling and ultimately BC aggressiveness [ 106 ]. The crosstalk between hypoxia and the ECM in orchestrating metabolic alterations through YAP/TAZ signaling has been demonstrated to play a role in cancer progression [ 107 ].…”

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

“…The role of HIF–1 in reshaping the topography of the ECM under hypoxia by collagen deposition and promoting the increased expression of remodelling enzymes such prolyl-4-hydroxylases and lysyl oxidases, which leads to ECM stiffness and metastasis, has been determined by studies. An increasing body of research indicates that hypoxia promotes the chemo-invasive and metastatic potential of breast cancer by activating metalloprotease 2 and 9 (MMP-2 and MMP-9), which also degrade ECM ( 31 – 33 ). According to multiple studies, hypoxic stress is expected to stimulate VEGF (Vascular Endothelial Growth Factor), a crucial regulator of angiogenesis ( 34 ).…”