Cutaneous squamous cell carcinoma (cSCC), a type of skin cancer, it’s the second most common type of skin cancer, after basal cell carcinoma and its incidence is increasing. It is estimated that cSCC accounts for nearly 25% of annual skin cancer deaths. Exposure to solar UV radiation is the predominant risk factor for this cancer. Approximately 3% to 5% of primary cSCCs metastasize, and the prognosis for patients with metastatic cSCC is poor. Although most cases are curable by excision of the primary tumor, a subset of patients develop aggressive and metastatic disease with few treatment options. Researchers have now identified C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cSCC.
The new study’s findings in The American Journal of Pathology, found that C5aR1 promotes the invasion of cSCC tumor cells. Its elevated presence suggests that C5aR1 might serve as a useful prognostic marker for metastatic disease and, potentially, a target for future therapies in advanced cSCC. Studies in multiple cancers have indicated that the complement system, which is a part of the human innate immune system and is a tumor-suppressing cytolytic mechanism, can also contribute to tumor progression and metastasis by inducing inflammation or causing immunosuppression. This prompted researchers to investigate the interaction between C5a and its protein receptor C5aR1 (which is found on the surface of cells) in cSCC.
Investigators noted that when C5a binds to C5aR1, it activates signaling pathways within the cell, leading to changes in cell behavior. The receptor couples to Gq type of G protein, which leads to the activation of another G protein (RhoA) that activates protein kinases related to cellular movememnts (ROCK-1). Galpha-q also activated the PI3K/c-AKT pro-survival signaling cascade that suppresses cell death and enhances metastatization. Scientists then examined C5aR1 in the context of cSCC progression and metastasis by combining in vitro 3D spheroid co-culture of cSCC cells and skin fibroblasts, human cSCC xenograft tumors grown in SCID (immunodeficient) mice and a large panel of patient-derived tumor samples of non-metastatic cSCC, metastatic cSCCs and cSCC metastases.
Researchers were surprised to find that fibroblasts influenced C5aR1 expression in cancer cells, and that the C5aR1 expression in stromal fibroblasts also had a role in metastasis and poor prognosis in cSCC. They also had not anticipated that C5aR1 expression would correlate with patient outcomes across a large clinical sample set. However, the results also suggest that C5aR1 could be a novel therapeutic target for the treatment of locally advanced and metastatic cSCC.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Heiskanen L et al. Amer J Pathol. 2025 Jun; 195(6):1158-1171.
Macaulay ARK et al. Brit J Dermatol. 2024 Dec; 192(1):104-117.
Nissinen L, Riihilä P et al. Sci Rep. 2024 Jun 12; 14(1):13465.
Viiklepp K, Nissinen L et al. J Invest Dermatol. 2022; 142(5):1478.
