Scientists headed by a team at the University of Tokyo have identified a protein, known as podoplanin (PDPN), that is common to both human and canine mucosal melanoma, and which appears to mobilize the cancer cells, allowing them to spread. The researchers hope that strategies for eliminating the protein could lead to a potential treatment for mucosal melanoma. Led by assistant professor Daiki Kato, PhD, at the University of Tokyo’s Laboratory of Veterinary Surgery, the researchers reported on their work in Molecular Cancer Research, in a paper titled “Podoplanin Drives Amoeboid Invasion in Canine and Human Mucosal Melanoma.” In their paper, the authors concluded, “PDPN could be used as a biomarker and a therapeutic target for the restriction of amoeboid invasion and metastatic dissemination in canine and human mucosal melanoma.”
Melanoma is a type of cancer that begins in the melanocytes, the pigments that give skin its range of tones. Skin cancer accounts for about 90% of all melanomas in humans, but a small percentage are mucosal melanomas, which can manifest in the body’s various mucosal linings such as in the nose. “Human mucosal melanoma is the most aggressive subtype of melanoma, and most patients develop an incurable metastatic disease, irrespective of surgical removal,” the team noted. Rare in humans, mucosal melanoma has a low survival rate. Hard to detect and even harder to treat—there is “little effective systemic therapy for human mucosal melanoma,” the authors noted—the five-year survival rate of mucosal melanoma is 25%, compared with 90% for common, cutaneous melanoma. Studying mucosal melanoma is also problematic, partly due to its rarity in humans, and partly due to the lack of analogous forms of cancer in animals.
In contrast with the rarity of human mucosal melanoma, canine mucosal melanoma is one of the most common oral malignancies in dogs, and is a highly aggressive tumor, the authors noted. Previous research had found that canine mucosal melanoma cells expressed podoplanin, a small transmembrane mucin-like glycoprotein, and also demonstrated that antibodies targeting podoplanin demonstrated antitumor efficacy in dogs with mucosal melanoma. “Even though mucosal melanoma is not so common in humans, it is very common in dogs,” said Kato. “There was no known connection between the two, but we have recently discovered something common to both. There is a protein that accompanies mucosal melanomas called podoplanin (PDPN). It’s a membrane protein, meaning it is involved in some functions on the surface of a cell.”
The team studied PDPN to see what might make it so potentially deadly. Their findings suggested that the protein can metastasize, or mobilize, otherwise static tumor cells. PDPN then effectively morphs tumor cells into something resembling a free-moving amoeba, which can squeeze between gaps in healthy tissue and move around to settle elsewhere in the body. This mechanism would explain why mucosal melanoma, in particular, can so quickly spread throughout the body. Interestingly, inhibiting PDPN in canine mucosal melanoma cells resulted in reduced cell proliferation, increased the proportion of apoptotic cells, and suppressed migratory and invasive capacity of the cancer cells. “Our study opens the possibility that PDPN plays a crucial role in amoeboid invasion and metastasis of canine and human mucosal melanoma,” the investigators stated.
The team then found that human patients with mucosal melanoma that exhibited a high level of PDPN succumbed to their cancer much sooner than individuals with less of the protein. “We further identified that PDPN expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with PDPN high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma,” the authors wrote. “These findings suggest that PDPN drives amoeboid invasion and metastasis in human mucosal melanoma through similar mechanisms as those acting in canine mucosal melanoma. Thus, naturally occurring canine mucosal melanoma could be a novel research model for PDPN expressing human mucosal melanoma.”
Kato said that researchers still need to understand the mechanism behind this podoplanin-related invasiveness. “A big challenge is actually our data. As mucosal melanoma is rare, there just isn’t a lot of human data to learn from; our study had to combine different data sets and is not as complete as we would like. However, our tests involving PDPN do confirm our suspicion. When we took mucosal melanoma samples from dogs and eliminated the PDPN, the resulting tumor released far fewer metastasized cells which could spread and cause more harm. Though the samples came from dogs, that part of the experiment was carried out in mice.”
The team concluded in their paper, “Overall, we propose that PDPN promotes canine and human mucosal melanoma metastasis by inducing aggressive amoeboid invasion and naturally occurring canine mucosal melanoma can be a novel research model for PDPN expressing human mucosal melanoma.”
The overall findings suggest that PDPN could represent a target for antibody therapy. If new drugs can eliminate PDPN in patients with mucosal melanoma, it might reduce the spread, and suffering, it causes. The team is working toward this now and aims to run clinical trials in dogs, within a few years.
“Of course, we will continue to work toward treatments for both canine and human cancers. PDPN is just one avenue of attack,” said Kato. “But also of great importance is the fact that we have found an animal model for an often fatal human cancer, which opens up many possibilities for study.”
