Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis

Abstract

Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential. Cancer Res; 76(16); 4828-40. Ó2016 AACR.

Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation

“…We also observed increased levels of p38 and phosphorylated p38 by western blot, and further confirmed the activation of MAPK pathway. This is consistent with previous reports indicating that LDL and VLDL could activate the MAPK pathway [14]. MAPK pathway activation has been widely recognized to play a vital role in the regulation of gene expression, mitosis, metabolism, cell proliferation, apoptosis and cellular movement [30].…”

“…Studies have also suggested that HFD may contribute to inflammation and oxidative stress by causing excessive production of reactive oxygen species (ROS) [13]; moreover, both LDL and VLDL were shown to activate the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway [14]. ROS are a group of molecules and free radicals generated within cells through oxygen metabolism.…”

Lipid Storage and Autophagy in Melanoma Cancer Cells

“…Such phenotype has been demonstrated in colorectal cancer where high levels of lipid droplets (LD) correlate with CD133 antigen (also known as prominin-1) expression level and Wingless-type MMTV integration site family (Wnt)/β-catenin pathway activation [8], making LD abundance a marker of colorectal CSC. A LD-loaded phenotype has also been observed in glioblastoma and in lung cancer where LD accumulation is associated to increased spheroid-forming capacity [10]. In addition, metastatic potential of melanoma FEMX-1 cell line has been reported to correlate with both CD133 and LD levels [11].…”

Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression

“…The HSPG, SDC2 binds Ezrin, a cytoskeletal protein (152) and serves as adapter molecules for IGF1 mediated activation of ERK (95). Additionally, HSPGs are implicated in lipoprotein uptake and cellular stress signaling (153, 154). As more researchers validate these findings, newer areas of HS- and HSPG-mediated regulation will be discovered.…”