Fluid Shear Stress enhances the metastatic potential of human colon cancer cells: A critical role of Nitric Oxide

Overview

Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer -related deaths worldwide. Despite therapeutic advances to treat the primary tumor, metastasis causes greater than 90% of cancer deaths. The role of Fluid Shear Stre ss (FSS) on colon cancer metastasis and whether this biomechanical force imparts any biochemical changes in the circulating colon cancer cells is not well understood. In this work, a bioengineering model is used to simulate the laminar FSS experienced by cancer cells using a parallel plate flow chamber. Exposure of HCT116 (human colorectal carcinoma cells) to physiological FSS stimulated metabolic activity, proliferation and colony formation. An in -depth mechanistic analysis identified nitric oxide (NO) as a crucial mechanosensory signaling molecule that confers the pro -oncogenic and pro -metastatic signal in HCT116 cells. Pretreatment with nitric oxide synthase (NOS) inhibitor, LNAME inhibited the FSS stimulated downstream pro -metastatic signature events. A systematic concentration curve analysis using NO donor, PAPA -NONOate, indicates that NO exerts a biphasic effect in colon cancer progression. Low NO concentration (1 -100 nanomolar) promotes colon neoplasms. However, at micromolar concentrations (˃1 mM), NO exerts cytotoxic effects and inhibits colorectal tumorigenesis. This raises the possibility of using serum nitrate/nitrite levels as a potential biomarker to aid in the early detection of colorectal cancer metastasis. Development of efficient drug delivery systems to deliver sustained high doses of NO directly to the primary tumor site may be effective in arresting primary tumor growth and delay or prevent colon cancer metastasis.

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

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