Signaling Pathways Linked to Cancer Seen as Overly Active in Systemic Sclerosis Patients

Genes and microRNAs that are a part of cancer-promoting signaling pathways are also overly active in systemic sclerosis (SSc) patients, possibly predisposing them to malignancies, a study reports.

The study, “Gene Profiling in Patients with Systemic Sclerosis Reveals the Presence of Oncogenic Gene Signatures,” was published in the journal Frontiers in Immunology.

SSc, a connective tissue disorder, is characterized by vasculopathy (disease of the blood vessels), immune system dysregulation, and fibrosis. Patients with SSc are known to have a higher-than-usual incidence of several types of cancer, particularly those of the breast, lung, and blood.

Some studies draw a link between cancer in SSc patients and the presence of particular autoantibodies (antibodies, or immune system proteins, that attack healthy organs and tissues). Otherwise, little is known about the link between cancer and SSc.

Researchers set out to investigate whether genetic factors play a role in promoting cancer in SSc patients, in order to better understand the factors that might raise their risk and help to identify those patients at greatest risk who need careful surveillance.

Using a technique called gene expression profiling, they determined the changes in gene expression in peripheral blood mononuclear cells (PBMCs) of patients with limited and diffuse types of SSc. PBMCs are any blood cell with a round nucleus, including such immune cells as monocytes, lymphocytes, and macrophages.

Numerous genes were found to be abnormally expressed, including many linked to the development of both SSc and cancer. (Gene expression is the process by which a gene instructs the synthesis of its products, often proteins.)

In particular, researchers found that genes involved in apoptosis (cell death), endothelial cell activation, extracellular matrix remodeling, immune response, and inflammatory pathways were poorly regulated. These pathways are associated with both SSc and various cancers.

As most genes work in concert with other genes, researchers did a network analysis of the abnormally expressed genes, and confirmed their previous observation that signaling pathways associated with cancer were present in patients’ PBMCs.

Altered expression of specific microRNAs (miR) — small RNA molecules that play a major role in gene expression — are well-established in both SSc and cancer. Therefore, researchers also looked at the expression profiles of miRs in the PMBCs collected.

They found  the activity of certain miRs — miR-21-5p, miR-92a-3p, miR-155-5p, and miR-16-5p — was significantly higher in SSc patients compared to healthy controls. These four miRs are also implicated in SSc development, and known to be upregulated (overly active) in several types of cancer — suggesting they also may be involved in cancer’s development in these patients.

Taken together, these results suggest that altered expression of genes and miRs can predispose SSc patients to cancer by activating cancer-promoting signaling networks.

As such, they “are important for a better risk stratification of patients and for the identification of a better individualized precision medicine strategy,” the researchers concluded.