Biological mechanisms that mediate the recurrence of lung cancer identified

Lung cancer is a major cause of death worldwide despite the recent introduction of immuno-cancer treatments. The survival and recurrence of remaining cancer cells after chemotherapy was unclear. Although the roles of cancer cells and interactions with other cells have been reported to contribute to the development and deterioration of cancer, research has been insufficient on the interaction of residual cancer and tumor microenvironment during the incubation period, and the resulting mechanisms to explain cancer recurrence.

A research team led by Professor Lee Ho-young of Seoul National University’s College of Pharmacy has isolated cancer cell subpopulations that survive chemotherapy among lung cancer cell lines and patient-derived lung cancer tissues, revealing the characteristics and survival mechanisms of cancer cells in these residual subpopulations. Furthermore, the research team proposed a method to identify the process of producing recurrent cancer through interaction with the tumor microenvironment and prevent cancer recurrence.

First, the team confirmed that cancer cells in these residual subpopulations divide very slowly compared to normal cancer cells in tumors, but their viability in barren environments such as energy sources/oxygen deficiencies is maximized.

Cancer cells are stressed in barren environments where oxygen or nutrition is reduced due to insufficient vascular production or anti-cancer drugs exist. To overcome this, the normal intracellular vesicles undergo various vesicle reactions. Typically, the expression of ordinary proteins is inhibited and specifically induces the expression of ATF4, which regulates the stress of the vesicles by inducing the maturation or decomposition of immature proteins. ATF4 mediates protein expression after stress relief to restore normal cell metabolism and division. On the other hand, it is also known that over-expression of ATF4 leads to apoptosis due to protein over-synthesis.

The researchers also revealed the process of inducing cancer recurrence and malignancy. 1)Low-growth cancer cells secrete various soluble factors such as cytokines, growth factors, and angiogenesis factors to introduce fibroblasts and vascular endothelial cells into tumor microenvironment. 2) Through signal activation such as COX2/PGE2 and Type 1 Collagen/Src, endothelial cells provide growth factors, oxygen, and energy sources for cancer cell division through vascular regeneration. 3) As a result, cell division in low-growth cancer cells is promoted.

Based on these mechanisms of action studies, researchers have proposed new treatments to prevent cancer recurrence: First, chemical anticancer drugs are used in combination with sildenafil (biagra), which is effective in promoting protein synthesis, to induce cell death after the resumption of division of low-growth cancer cells. Second, clinically applicable COX2, Src, and EGFR target anticancer drugs stimulate fibroblasts or endothelial cells to prevent growth/division of low-growth cancer cells.

The research team expects that if the preclinical and clinical studies prove the validity of the treatment strategy proposed in this study, this study will be used as a new treatment to increase the survival rate of cancer patients by suppressing cancer recurrence.


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