Clotting Factor Associated With Greater Metastases in Certain Lung Cancers

Immune cells that promote clotting within tumors in a specific type of lung cancer are actually assisting the tumor to spread throughout the body, according to a recent study published in Nature Communications.

Research in the lung squamous carcinomas (LUSC) space, which accounts for about 30% of lung cancer diagnoses, has not seen recent advances in treatment. However, in previous studies, the therapeutic blockade of immune checkpoints in patients with LUSC demonstrated encouraging responses.

In a molecular profiling analysis based on The Cancer Genome Atlas (TCGA), data showed that LUSC tumors are idiosyncratic and do not appear to be driven by solitary actionable pathways. Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center used a microarray analyses of LUSC and identified 4 gene expression subtypes: classical, basal, primitive, and secretory.

Specifically, the secretory subtype was defined by an immune response signature of genes associated with inflammation, complement activation, and immune cell recruitment. Using this finding, researchers analyzed the LUSC TCGA dataset and discovered a new and previously overlooked subset of patients with LUSC that is highly associated with inflammatory monocyte (IM) infiltration and poor survival rates.

“The way that these immune cells promote lung cancer metastases was very unexpected. They produce a large amount of a factor that leads to clot in the tumor, which the tumor cells can latch onto and climb across to spread in the body,” study author Chad Pecot, MD, assistant professor at the University of North Carolina School of Medicine division of hematology/oncology, said in a statement.

The IM cells, which usually help to promote clotting and assist in wound healing, also make it possible for tumor cells to metastasize and spread to other parts of the body. The analysis showed that the CD14 biomarker and the IM-prevalent subset was associated with poor survival of LUSC patients.

The tumors exhibit a signal called CCL2, which helps to attract IMs. The IMs then release clotting factor XIIIA, which creates a “fibrin scaffold that helps tumor cells climb across and travel to distant organs,” said Pecot in a statement.

Researchers targeted the main CCL2 cell surface receptor by genetically modifying the expression of CCL2 in a metastasis model. The modification indicated that low expression was linked to reduced metastases, while high expression was linked to greater metastases. In addition, researchers discovered that the presence of a clot made it easier for cancer cells to migrate around the body.

In order to address this finding, the study authors sought to reduce metastases by using a compound that blocks CCR2, a receptor found on the surface of IMs. This method identified a significant decrease in lung metastases.

“These results shed new light on tumor microenvironment functioning and, potentially, may lead to new approaches for targeting the metastases of this extremely aggressive disease,” said lead study author Alessandro Porrello, PhD, researcher and University of North Carolina Lineberger and a study author.

As far as next steps, researchers have noted that this strategy should be further investigated; as well as potentially other methods of clotting prevention within tumors to identify if it not only prevents metastases but can inhibit the process once it begins.

Reference

Porello A, Leslie P, Harrison E, et al. Factor XIIIA­—expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking. [published online May 18, 2018]. Nat Commun. doi:10.1038/s41467-018-04355-w.