CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling

Abstract

CD44, an abundantly expressed adhesion molecule, and its alternative splice variants have been associated with tumorigenesis and metastasis. In the context of gastric cancer (GC), de novo expression of CD44 variant 6 (CD44v6) is found in more than 60% of GCs, but its role in the pathogenesis and progression of this type of cancer remains unclear. Using a combination of media conditioning experiments and decellularized extracellular matrices (ECMs), this study investigates the hypothesis that CD44v6 overexpression enhances tumor cell malignant behavior by modulating stromal cell-mediated ECM remodeling. Our findings indicate that soluble factors secreted by CD44v6 expressing GC cells particularly increase proliferation and myofibroblastic differentiation of adipose stromal cells (ASCs). These changes in ASC phenotype mediate the deposition of fibrotic/desmoplastic ECM that, in turn, stimulates GC proliferation and inhibits GC clustering. Pharmacological inhibition of matrix metalloproteinase (MMP) activity in tumor cells abrogated matrix-induced changes in tumor cell malignant behavior. Additionally, studies in mice confirmed the pathological relevance of CD44v6 expression and consequential changes in ECM remodeling to gastric tumorigenesis in vivo. Collectively, these results indicate a direct link between CD44v6, ECM remodeling, and GC malignant behavior opening new insights into potential CD44v6-targeted therapies.

Engineering Modular Half-Antibody Conjugated Nanoparticles for Targeting CD44v6-Expressing Cancer Cells

“…Tumor-conditioned media (TCM) was prepared as previously described [ 16 ]. In brief, MKN74 and CD44v6 cells were cultured as above until 90% confluence, rinsed with phosphate buffered saline (PBS, pH 7.4), and then incubated with low serum media (DMEM, 1% FBS, 1% Pen/Strep).…”

“…In the stomach, we have shown that CD44v6 is considerably de novo expressed in gastric pre-malignant and malignant lesions (more than 60% of all GCs), while the normal gastric mucosa remains negative for this marker [ 14 ]. Additionally, we have recently demonstrated that CD44v6 has been correlated with poor prognosis [ 15 ] and aggressive behavior of the disease [ 16 ], suggesting its value not only for early diagnosis but also for prognosis and as a therapeutic target in GC.…”

“…Bioorthogonal Michael-addition click chemistry was employed for the site-specific conjugation of CD44v6 half-antibody to maleimide-modified PNPs. Finally, the ability of the CD44v6 half-antibody-conjugated PNPs to selectively bind to CD44v6-expressing GC cells was demonstrated using an isogenic human GC cell line, previously established and explored by our group [ 15 , 16 , 23 ]. Overall, this study provides new insights for the development of more effective GC-targeting diagnostic and therapeutic approaches and emphasizes the modular and bioorthogonal nature of our strategy that can be broadly applied to develop novel targeted approaches.…”

Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages

“…Decellularization was achieved as previously described. 12,58 Briefly, ASC cultures were washed with phosphate-buffered saline and subsequently incubated in 0.5% Triton-X þ 200 mmol/L NH 4 OH, 12,59,60 followed by incubation in 1 U/mL DNase (VWR Amresco, Radnor, PA) at 37 C to remove cellular membranes, organelles, and nucleic acids. After decellularization, maintenance of native matrix structure and key compositional components was confirmed by immunofluorescence analysis of Fn (Millipore-Sigma, St. Louis, MO; F7387) and collagen type I (Abcam; ab34710) via confocal microscopy (Zeiss, Pleasanton, CA; 710) and image analysis.…”

Identification of genes related to low‐grade glioma progression and prognosis based on integrated transcriptome analysis

“…Recently, some researchers have found that extracellular matrix (ECM) molecules, such as collagen proteins, laminins, and fibronectin, are pivotal for the progression of tumors, including breast cancer, pancreatic cancer, gastric cancer, glioma, and so on. And the ECM interaction pathway also can participate in the invasion of glioma, especially its role in regulating the mobility of the cells .…”