Aberrant Mitochondrial Iκbα/NF-Κb-Signaling in Lung Cancer Cells Mediates Endothelial Cell Activation and Platelets Aggregation, Facilitating Lung Cancer Metastasis and Cancer-Associated Thrombosis

Cancer presents a significant risk of blood clot formation in cancer patients, impacting patient outcomes. The intricate relationship between cancer-associated thrombosis and metastasis involves multifaceted mechanisms, including a hypercoagulable state, endothelial dysfunction, platelet activation, and interaction with the coagulation system, alongside inflammatory and immune responses. Here, we aim to unveil the non-cell autonomous pathways driving endothelial activation, platelet aggregation, and pro-thrombotic terrain for metastatic fomentation in a murine model of lung cancer.

The inhibitor IκBα, a regulator of the p65-NF-κB signaling pathway, plays a pivotal role in cancer metastasis. Our previous research identified IκBα overexpression in lung cancer, highlighting its potential role in the tumor's pathogenesis. To delve deeper into the role of mitochondrial IκBα, we engineered a construct specifically targeting it to the mitochondria (IκBα-MTS) of cancer cells. Intriguingly, lung cancer cells expressing IκBα-MTS displayed increased aggressiveness, as measured by their capability to increase proliferation, reducing apoptotic response and inducing migration.

Additionally, mitochondrial IκBα led lung cancer cells to activate endothelial cells (ECs), promoting an inflammatory and adhesive state, ultimately priming ECs at the metastatic site to facilitate cancer cells intravasation. This mechanism may be attributed to the metabolic shift observed in lung cancer cells with IκBα-MTS compared to those with wild-type IκBα, related to the induction of mitochondrial dysfunction.

In response to this environment, ECs were conducive to cancer-associated thrombosis, characterized by a hypercoagulable state resulting from the release of the procoagulant factors vWF, and favoring platelet activation and aggregation. Simultaneously, this facilitated cancer cell intravasation and metastasis.

Therefore, our findings offer crucial insights into “thrombo-oncotic” mechanisms and underscore the significance of ECs activation, microthrombi and metastasis formation as potential therapeutic targets in cancer treatment.

No relevant conflicts of interest to declare.