Abstract
Up to 50% of head and neck squamous cell carcinoma (HNSCC) patients have lymph node (LN) metastasis, resulting in poor survival rate. Numerous studies have supported the notion that the alterations of gene expression and mechanical properties of cancer cells play an important role in cancer metastasis. However, which genes and how they regulate the biomechanical properties of HNSCC cells to promote LN metastasis remains elusive. In this study, we used an LN-metastatic mouse model in vivo to generate an LN-metastatic head and neck squamous cell carcinoma cell line and compared the differences in the biomolecular and biomechanical properties of LN-metastatic and non-metastatic cells. Our results showed that LN-metastatic cells had a higher level of Snail expression compared to non-LN-metastatic cells. The higher Snail expression promoted the cellular invasion capability in confined environments, mainly by increasing the longitudinal strain of the cell nuclei, which could be attributed to the stronger cell traction force and softer nuclear stiffness. These two biomechanical changes were correlated, respectively, to a larger amount of focal adhesion and less amount of nuclear lamins. Taken together, our works revealed not only the biomechanical profiles of LN-metastatic cells but also the corresponding biomolecular expressions to pinpoint the key process in LN metastasis.
Highlights
Lymph node (LN) metastasis is the major risk and cause of deaths in patients with head and neck squamous cell carcinoma (HNSCC) (Noguti et al, 2012)
We further examined the expression of Snail in SAS-LN and SAS cells and found that Snail expression was higher in SAS-LN (LN-metastatic cells), supporting the notion that Snail is crucial for the alterations of biomolecular and the corresponding biomechanical properties of cancer cells for LN metastasis
A lymph node metastatic mouse model system was used to generate LN-metastatic human HNSCC cells (SAS-LN), which were isolated from lymph nodes of nude mice in 4 weeks after tongue injection with non-metastatic HNSCC cells (SAS)
Summary
Lymph node (LN) metastasis is the major risk and cause of deaths in patients with head and neck squamous cell carcinoma (HNSCC) (Noguti et al, 2012). Up to 50% of HNSCC patients have LN metastasis in which cancer cells detach from primary tumor tissues (oral, tongue, or throat site), invade into surrounding extracellular matrices (ECMs), spread to lymph nodes, damage the lymph nodes, and further metastasize to regional nodes (Shah et al, 1990). The vascular endothelial growth factor-C (VEGF-C) secreted from malignant tumor cells is the major regulator in tumorinduced lymphangiogenesis to promote LN metastasis (Hirakawa et al, 2007; Kudo et al, 2012; Chen et al, 2013). The VEGF-C enhances the formation of tumor lymphatic vessels surrounding tumors and activates the integrin α4β1 on the endothelium of the tumor lymphatic vessels which interacts with vascular cell adhesion molecule 1 (VCAM-1) to promote cancer cell migration and LN metastasis (GarmySusini et al, 2013). The change in the biomechanical properties of HNSCC cells during LN metastasis remains elusive, and how Snail regulates the corresponding mechanical properties of cancer cells to promote LN metastasis has attracted much less attention
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