Tumor matrix stiffness provides fertile soil for cancer stem cells

Abstract

Matrix stiffness is a mechanical characteristic of the extracellular matrix (ECM) that increases from the tumor core to the tumor periphery in a gradient pattern in a variety of solid tumors and can promote proliferation, invasion, metastasis, drug resistance, and recurrence. Cancer stem cells (CSCs) are a rare subpopulation of tumor cells with self-renewal, asymmetric cell division, and differentiation capabilities. CSCs are thought to be responsible for metastasis, tumor recurrence, chemotherapy resistance, and consequently poor clinical outcomes. Evidence suggests that matrix stiffness can activate receptors and mechanosensor/mechanoregulator proteins such as integrin, FAK, and YAP, modulating the characteristics of tumor cells as well as CSCs through different molecular signaling pathways. A deeper understanding of the effect of matrix stiffness on CSCs characteristics could lead to development of innovative cancer therapies. In this review, we discuss how the stiffness of the ECM is sensed by the cells and how the cells respond to this environmental change as well as the effect of matrix stiffness on CSCs characteristics and also the key malignant processes such as proliferation and EMT. Then, we specifically focus on how increased matrix stiffness affects CSCs in breast, lung, liver, pancreatic, and colorectal cancers. We also discuss how the molecules responsible for increased matrix stiffness and the signaling pathways activated by the enhanced stiffness can be manipulated as a therapeutic strategy for cancer.

Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets

“…EAC PDOs were embedded in NorHA hydrogels with mechanical properties that ranged from a “soft” hydrogel (0.5 mg/mL VPM; G′ = 100 Pa, similar to Matrigel) to a “stiff” hydrogel (1.2 mg/mL; G′ = 1000 Pa, similar to tumor ECM) and cultured for 14 days. Importantly, the mechanical properties of our stiff hydrogel have been shown to promote protumorigenic behavior in normal cells in previous in vitro studies ( 38 , 39 ) and compare favorably with measurements of human tumor stiffness (G′ ≥ 1,000 Pa) ( 38 , 40 – 42 ). EAC PDOs embedded in stiff (G′: 1,000 Pa) NorHA hydrogels showed significant increases in the size (area) and formation (density) of organoids formed per hydrogel as a function of matrix stiffness ( Figure 2, A–C ).…”

Cellular elasticity in cancer: a review of altered biomechanical features

“…In a variety of solid tumors, matrix stiffness—a mechanical property of the ECM increases in a gradient pattern from the tumor core to the tumor periphery and can stimulate treatment resistance, invasion, proliferation, metastasis, and recurrence. 95 The stiffness and elasticity of ECM vary from tissue to tissue. The ECM's elasticity can vary by several orders of magnitude.…”

Phenotypic Heterogeneity, Bidirectionality, Universal Cues, Plasticity, Mechanics, and the Tumor Microenvironment Drive Cancer Metastasis

“…Matrix stiffness also has an impact on CSC function, as it causes the activation of mechanosensitive cell surface receptors that subsequently activate mechanosensory and/or mechanoregulatory molecules including integrins, vinculin, talin, paxillin, FAK, and YAP [211]. The mechanoregulatory molecules can alter both cancer cells and CSCs by impacting various signal transduction cascades [212]. For example, FAK is able to trigger via the integrin-FAK-Src signal transduction pathway the activation of serine/threonine-protein kinase (AKT), β-catenin (Wnt signaling pathway), cyclin D1, ERK (Ras-ERK signaling pathway), JNK (RhoA-JNK pathway), phosphatidylinositol-3-kinase (PI3K), and other proteins, whereas tumor suppressing genes like phosphatase and tensin homolog (PTEN) and glycogen synthase kinase 3α/β (GSK3α/β) are blocked [213,214].…”