Novel prognostic biomarker for metastatic skin cancer prediction and treatment
A protein-linked receptor has been identified as a novel prognostic biomarker and potential therapeutic target for metastatic skin cancer.
A research team from the University of Turku and Turku University Hospital (both Finland), led by Veli-Matti Kähäri, has identified a novel biomarker — C5aR1 — for predicting metastasis risk and poor prognosis in skin cancer patients. These results highlight how the protein-linked receptor could serve as a prognostic marker for metastatic disease as well as a therapeutic target.
In recent decades, an increased incidence of cutaneous squamous cell carcinoma (cSCC), the most common type of metastatic skin cancer, has been seen. While only 3–5% of primary cSCC cases metastasize, they account for nearly 25% of annual skin cancer deaths. Despite this, there are currently no established molecular markers in clinical practice for predicting the risk of metastasis.
“…There is an urgent need for predictive biomarkers for the prognosis of cSCC and for new therapeutic targets for metastatic cSCC,” stated Kähäri.
The complement system — an integral part of the human innate immune system, which has conventionally been viewed as a tumor-suppressing cytolytic mechanism — has been indicated in several studies to contribute to tumor progression and metastasis. For instance, the complement component C5a, which acts as a signaling molecule in cancer, and its protein-linked receptor C5aR1, which is found on the surface of target cells, have both been indicated in several cancers, either for overexpression or poor prognosis. However, C5a and C5aR1’s role in the progression and metastasis of cSCC has not been fully investigated, prompting the team to investigate their interaction.
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The team noted that C5a binding to C5aR1 activates signaling pathways within the cell, which leads to changes in cell behavior. To study this in the context of cSCC progression and metastasis, they combined an in vitro 3D spheroid co-culture of cSCC cells and skin fibroblasts, human cSCC xenograft tumors grown in severe combined immunodeficiency mice, and a large panel of patient-derived tumor samples of non-metastatic cSCC, metastatic cSCCs and cSCC metastases.
The results showed increased expression of C5aR1 in cSCC cells that were co-cultured with human skin fibroblasts in 3D spheroids, and increased invasion of cSCC cells exposed to recombinant C5a. Surprisingly, the researchers found that fibroblasts in the tumor microenvironment induced C5aR1 expression in cSCC tumor cells. Additionally, this elevated expression of C5aR1 in cSCC tumor cells and stromal fibroblasts was associated with metastasis and poor prognosis, which correlated with patient outcomes across the large clinical sample set and highlights the potential of C5aR1 as a prognostic biomarker.
“Our findings suggest that C5aR1 is a potential metastatic risk marker, a novel prognostic biomarker, and a promising therapeutic target for cSCC,” commented co-authors Pilvi Riihilä and Liisa Nissinen.
