Understanding Skin Cancer: Research Progress and Implications

Rising Incidence of Skin Cancer

Skin cancer rates are increasing, particularly for cutaneous squamous cell carcinoma (cSCC), the second most prevalent non-melanoma skin cancer in the United States. Approximately 2-5% of cSCC patients may develop metastatic disease, where cancer spreads to other body parts and has a higher chance of recurrence. cSCC typically manifests as scaly patches, open sores, or warts and is more likely to occur on skin areas exposed to UV radiation from sunlight or tanning beds. The rise in skin cancer incidence is partly attributed to indoor tanning.

Complex Development of Skin Cancer

The process of skin cancer development is intricate, and researchers are making strides in understanding the proteins and their interactions that contribute to this disease. Mouse models are utilized to induce tumor formation chemically with known carcinogens. A study conducted by researchers from American University in Washington, DC, has shed light on signaling pathways associated with cancer development and progression. Dr. Kathleen DeCicco-Skinner and colleagues published their findings in the January 2019 issue of Oncogenesis, highlighting the role of the HGF/MET signaling pathway in skin cancer development and identifying a potential therapeutic drug to inhibit this pathway.

The Role of the Tpl2 Gene

Previous research by Dr. DeCicco-Skinner’s team indicated that mice lacking the Tpl2 gene showed a significantly increased incidence of skin tumors. Their current study builds on these findings, confirming that Tpl2 acts as a strong tumor suppressor. Skin cells from mice deficient in Tpl2 demonstrated increased growth and conversion to cancerous cells. The rate of tumor development in Tpl2-deficient mice exposed to carcinogens was double that of mice with the Tpl2 gene, emphasizing its critical role in tumor suppression.

Cellular Processes Affecting Tpl2 Activity

The research delved deeper into the cellular pathways that support the tumor-suppressing function of Tpl2. The involvement of fibroblast cells in tumor development led the team to investigate the HGF/MET signaling pathway. HGF, produced by fibroblast cells, facilitates communication between primary tumors and fibroblast cells within the tissue’s connective framework. When HGF binds to the MET protein, it activates a series of signaling pathways that regulate cell division, proliferation, and tissue invasion.

Cancer Cells and the MET Protein

While MET activation is essential during embryonic development for tissue formation, cancer cells exploit this mechanism to invade surrounding tissues and spread the disease.

Capmatinib: A Promising Therapeutic Development

The HGF/MET protein pair is implicated in various cancers, making it a target for novel cancer therapies. Novartis has developed capmatinib, a drug that inhibits MET activity, currently under investigation in clinical trials for lung, kidney, and liver cancers. The recent study indicated that capmatinib treatment reduced tumor numbers by 60% in Tpl2-deficient mice, with none of the Tpl2 mice developing malignant tumors when treated. These findings underscore the significance of the MET signaling pathway in Tpl2’s tumor-suppressing role. Additional experiments revealed that Tpl2-deficient mice were resistant to the effects of TGFβ, a potent growth inhibitor.

Future Directions and Human Trials

Mouse models remain invaluable for cancer research, but results must be validated in human clinical trials. The study found no adverse health effects, such as weight loss, associated with capmatinib treatment; however, human studies are essential to confirm the safety and effectiveness of this drug.

Significance of the Study Results

These findings represent a significant advancement in understanding the cellular mechanisms underlying skin cancer. Nevertheless, questions remain, particularly regarding the activation of the HGF/MEK pathway in the absence of Tpl2. Dr. DeCicco-Skinner emphasized the need to explore protein interactions to effectively target the development and spread of cancers like squamous cell carcinoma.

References

Bonan NF et al., Inhibition of HGF/MET signaling decreases overall tumor burden and blocks malignant conversion in Tpl2-related skin cancer, Oncogenesis, 2019, 8 (1).
Unraveling the genetic causes of skin cancer. Retrieved from https://www.eurekalert.org/pub_releases/2019-01/au-utg011319.php
Symptoms of squamous cell carcinoma and contributing factors to development retrieved from https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma
Gentile A and Comoglio PM, Invasive growth: a genetic program, Int. J. Dev. Biol., 2004, 48: 451-456.