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Review
. 2024 Mar 13:12:1335636.
doi: 10.3389/fcell.2024.1335636. eCollection 2024.

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis

Sun-Ah Lee #  1 , Gi-Ju Cho #  1 , Doyoung Kim  1 , Dong-Hwee Kim  1   2   3
Affiliations
Review

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis

Sun-Ah Lee et al. Front Cell Dev Biol. .

Abstract

Mechanical properties of the tumor microenvironment play a critical role in cancer progression by activation of cancer mechano-responses. The biophysical interactions between cancer cells and their dynamic microenvironment are attributed to force-dependent alterations in molecular pathways that trigger the structural reorganization of intracellular organelles and their associated genetic modifications. Recent studies underscore the role of oxygen concentration in cancer metastasis. Suppressed oxygen levels promote the development of invasive phenotypes and aggressive proliferation of cancer cells, accompanied by remodeling of tumor microenvironment encompassing the modulation of physical settings of extracellular matrix. This review summarizes the role of biophysical interactions between cancer cells and their surroundings in determining cancer progression. Biophysical interpretation of the tumor microenvironment and cancer progression could provide further insights into the development of novel biomedical technologies for therapeutic cancer treatment.

Keywords: ECM remodeling; cancer biophysics; cancer metastasis; hypoxia; mechano-regulation; mechano-signaling; tumor-microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Biophysical interplay between ECM remodeling and hypoxia signaling in regulating cancer progression. Biophysical relationship between ECM remodeling and hypoxia-induced signaling pathways plays an important role in regulating cancer progression. Physical cues in 3D ECM including fiber diameter and alignment as well as pore size and viscoelasticity of the ECM regulates hypoxia-induced biochemical pathways, resulting in progression of metastatic alteration.
FIGURE 2
FIGURE 2
Biophysical interactions between cell and extracellular environments. (A) Specific cell-matrix interactions are due to different integrin ligands and FAK activity. Both influence front-rear polarization and organelle rearrangement on anisotropic micropatterns. Representative immunofluorescence images of U-251MG cells on crossbow-shaped micropatterns coated with diverse ECM components or integrin β1-_targeting monoclonal antibodies. ROIs depict centrosomes (white arrows), visualized by staining of γ-tubulin and paxillin. Front-rear polarization was evaluated based on the orientation of the perinuclear centrosome, indicated by γ-tubulin or centrin-2, relative to the nucleus. Scale bar: 10 μm and 3 μm (ROI). Copyright obtained from reference [Aleksi Isomursu et al., Small methods (2023)]. (B) NIH3T3 cells adapts their surrounding environments to navigate through restrictive space. Top views and side views of confocal laser scanning microscopy images of cells extending protrusion along the sharp edges of the portions of the grooves on the micropatterns. Blue arrows indicate the cell nuclei. NIH3T3 cells can navigate complex, confined 3D spaces via morphological adaptations Scale bar: 20 μm. Copyright obtained from reference [Yusuke Shimizu et al., Advanced Biosystems (2020)]. (C) Collective cells in spheroids move directionally towards each other. All aggregating cell lines including a human prostate cancer cell line (PC-3), epithelial human breast cancer cell line (MDA-MB-231), primary renal cancer cell line (ACHN), osteosarcoma cell line (MG-63), lung cancer cell line (NCI-H23), gastric cancer cell line (Hs746T) recapitulate the same behavior observed in aggregation assays either starting from single cells or from spheroids. The fraction of aggregating cells was calculated by manually screening all cells appearing in the first frame. Scale bar: 500 μm. Copyright obtained from reference [Miriam Palmiero et al., Molecular Oncology (2020)].
FIGURE 3
FIGURE 3
Glucose, lipid, and amino acid metabolism pathways and integrin-mediated mechanotransduction by HIF signaling. Transmembrane protein integrins serve as molecular linkage between the ECM in the extracellular space and cytoskeletal network in the intracellular cytoplasmic space, facilitating the transmission of mechanical forces induced by the actin retrograde flow via mechanosensitive focal adhesion proteins. Hypoxia directly regulates ECM composition through the enzymes. Furthermore, HIF signaling regulates glucose, lipid, and amino acid metabolic pathways in cellular metabolism under hypoxic conditions. This demonstrates how HIF signaling regulates cellular metabolism in hypoxia and highlights the tight relationship between these pathways and cancer progression. Within these pathways, the TCA cycle, glutamine metabolism, and NADH production play important roles, further highlighting the complex relationship between HIF signaling and cellular metabolism.
FIGURE 4
FIGURE 4
YAP/TAZ signaling pathways in hypoxia. (A) Depletion of amino acid transporters (AATs including SLC1A5/ASCT2, SLC7A5/LAT1, and SLC38A2/SNAT2) inhibits the activation S6 ribosomal protein (pS6), a downstream _target of mTOR pathway. Representative western blot images show the changes in the protein expression of AATs, total- and phospho-S6 ribosomal protein in HCT116 and DLD-1 cells after the shRNA transfection. β-actin was used as protein loading control. Copyright obtained from reference [Kandasamy P et al., Molecular Oncology (2021)]. (B) Y/T-TEAD transcriptional activity is increased in CSC CD44-positive cells. Representative images of YAP1 and CD44 detection by immunohistochemistry performed on 3 μm serial tissue sections of human primary Gastric Cancer. GC20, GC04 and GC44 are intestinal histological subtype GC; GC06 is a diffuse type GC. Scale bar: 50 μm. Copyright obtained from reference [Giraud J, et al., International Journal of Cancer (2020)] (C) Verteporfin inhibits the expression of CSC markers in GC cell lines and patient-derived primary GC xenografts (PDX). Representative images of CD44 expression and ALDH activity determined by immunofluorescence analysis on live GC10-treated tumorspheres. CD44 staining, ALDH activity, and the nuclei were marked red (using anti-CD44-APC antibodies), green (using the ALDEFLUOR reagent), and blue (using DAPI), respectively. Scale bar: 10 μm. Copyright obtained from reference [Giraud J, et al., International Journal of Cancer (2020)].
FIGURE 5
FIGURE 5
Substrate stiffness regulates tumor immunosuppression and progression. (A) EMT, TGFβ1, and PDL1 expression increased proportionally with the rise in matrix stiffness. Western blot detects the expression of EMT markers (E-cadherin, Vimentin), TGFβ1, and PDL1 in cystic fibrosis pancreatic adenocarcinoma cells (CFPAC) and KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-1-Cre cells (KPC) cultured in 3D culture systems with varying matrix rigidity ranging from 1 to 20 kPa. Copyright obtained from reference [Zhang, Haoxiang, et al., Bioengineering and Translational Medicine (2023)]. (B) Multiplex IHC staining evaluating collagen production (Masson staining), EMT status (E-cadherin), and cell proliferation (Ki-67) in murine pancreatic ductal adenocarcinomas (PDAC) tumor tissues with varying degrees of matrix rigidity reveals that increasing ECM rigidity induces enhanced EMT and cell proliferation. Scale bar: 200 μm. Copyright obtained from reference [Zhang, Haoxiang, et al., Bioengineering and Translational Medicine (2023)]. (C) Extracellular matrix rigidity promotes immunosuppression by decreasing anti-tumor lymphocyte presence and upregulating presence of immunosuppressive cells and expression of marker proteins of the PDAC tumor. Using multiplex IF staining to map the TME of in different matrix rigidity murine PDAC tumors tissues include exhaust CD8+ cytotoxic T (CD8+PD1+), CD4+ T cells (CD4+), macrophages (F4/80+), M2 macrophages (F4/80+CD206+), TGFβ1/PDL1 expression and EMT status (Vimentin and α-SMA). Scale bar: 200 μm. Copyright obtained from reference [Zhang, Haoxiang, et al., Bioengineering and Translational Medicine (2023)]. (D) Increased matrix rigidity enhances the polarization of M2 macrophages in hepatocellular carcinoma cells (HCC). Two-color immunofluorescence staining for CD68 and CD163 (biomarkers for M2 macrophages) was performed on a tissue microarray obtained from buffalo rat models of HCC with varying liver stiffness backgrounds. Scale bar: 50 μm. Copyright obtained from reference [Xing, Xiaoxia, et al., The FEBS Journal 288.11 (2021)].
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. DK was supported by the National Research Foundation of Korea (NRF-2022M3H4A1A03067401, 2V09840-23-P024, RS-2023-00251315, RS-2023-00221182, 2021R1A5A2022318) and ICT Creative Consilience Program through the Institute of Information and Communications Technology Planning and Evaluation (IITP) grant funded by the Korea government (MSIT) (IITP-2024-2020-0-01819). This study was supported by the KU-KIST Graduate School of Converging Science and Technology.

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