Shed Skin Cancer, Not Collagen XVII: A New Approach to Targeting Skin Cancer Progression
Authors: Olivier Gaide, Daniel Hohl
Journal: Molecular Therapy (2017)

Squamous cell cancer (SCC) is shaping up to become the next big challenge in skin cancer. Efforts to characterize the molecular mechanisms leading to tissue invasion and metastasis by SCC are of key interest. In this issue of Molecular Therapy, Galiger et al.1Galiger C. Löffek S. Stemmler M.P. Kroeger J.K. Mittapalli V.R. Fauth L. Esser P.R. Kern J.S. Meiss F. Laßmann S. et al.Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression.Mol Ther. 2017; 26 (this issue): 17-30Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar reveal a dual role of collagen XVII to drive both SCC proliferation and tissue invasion. They further show that these effects may be blocked by monoclonal antibodies targeting different parts of this protein. The frequency of SCC is second only to basal cell cancer (BCC) in humans. Its incidence is on the rise in most countries, and this increase also applies to advanced forms of SCC, including metastatic SCC.2Karia P.S. Han J. Schmults C.D. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012.J. Am. Acad. Dermatol. 2013; 68: 957-966Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar The care of small SCCs is often trivial, but older age increasingly leads patients to delay therapy until excisions are difficult to manage, requiring complex surgery or radiotherapy. Multiplicity of SCCs and BCCs is another cause of delayed care, as patients easily tire of their regular check-ups, which are often followed by skin surgery. This is especially the case for immune-compromised patients, no matter the cause, and those suffering from chronic lymphatic leukemia and organ transplant recipients.3Mehrany K. Weenig R.H. Lee K.K. Pittelkow M.R. Otley C.C. Increased metastasis and mortality from cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia.J. Am. Acad. Dermatol. 2005; 53: 1067-1071Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 4Mehrany K. Weenig R.H. Pittelkow M.R. Roenigk R.K. Otley C.C. High recurrence rates of squamous cell carcinoma after Mohs’ surgery in patients with chronic lymphocytic leukemia.Dermatol. Surg. 2005; 31 (discussion 42): 38-42Crossref PubMed Scopus (72) Google Scholar When such cancers progress along nerves (peri-neural invasion) or become metastatic, surgery and radiotherapy may no longer be an option. These patients, who we are seeing with increasing frequency in our clinics, have taught us that metastatic SCC has a worse prognosis than metastatic melanoma. In our opinion, few have yet fully appreciated this problem. Therefore, the new findings described in this issue of Molecular Therapy are important, because they yield new clues about the mechanisms leading to SCC invasion and metastasis and, even more importantly, suggest innovative ways to exploit them at the bedside. Why does metastatic SCC come with a worse prognosis than melanoma? The first reason is the outstanding progress that has been made in the treatment of melanoma, which has been the focus of much research in the preceding decades. This has led to the development of small molecules targeting Braf, Nras, and c-Kit with proven clinical efficacy.5Luke J.J. Flaherty K.T. Ribas A. Long G.V. Targeted agents and immunotherapies: optimizing outcomes in melanoma.Nat. Rev. Clin. Oncol. 2017; 14: 463-482Crossref PubMed Scopus (737) Google Scholar Research on cutaneous SCC, on the other hand, has been largely overlooked and has received less attention from both the industry and funding bodies. As a result, there are no targeted therapies for this type of cancer. Drawing parallels with head and neck SCC, clinicians have used anti-epidermal growth factor receptor (EGFR) antibodies either as a single agent or in combination with alkylating chemotherapy, but reports on the efficacy of this agent are quite limited.6Stratigos A. Garbe C. Lebbe C. Malvehy J. del Marmol V. Pehamberger H. Peris K. Becker J.C. Zalaudek I. Saiag P. et al.European Dermatology Forum (EDF)European Association of Dermato-Oncology (EADO)European Organization for Research and Treatment of Cancer (EORTC)Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline.Eur. J. Cancer. 2015; 51: 1989-2007Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar Invasive cutaneous SCC is characterized by the loss of adhesion molecules, such as E-cadherin, indicating that they have undergone the process of epithelial mesenchymal transition.7Toll A. Masferrer E. Hernández-Ruiz M.E. Ferrandiz-Pulido C. Yébenes M. Jaka A. Tuneu A. Jucglà A. Gimeno J. Baró T. et al.Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases.J. Dermatol. Sci. 2013; 72: 93-102Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar In this new study, Galiger and colleagues1Galiger C. Löffek S. Stemmler M.P. Kroeger J.K. Mittapalli V.R. Fauth L. Esser P.R. Kern J.S. Meiss F. Laßmann S. et al.Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression.Mol Ther. 2017; 26 (this issue): 17-30Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar provide evidence that collagen XVII cleavage and shedding play a key role in SCC progression. Collagen XVII is a transmembrane protein that is key to maintaining the linkage between intracellular and extracellular structural elements involved in epidermal adhesion. Two homotrimeric forms of type XVII collagen exist: a full length transmembrane form and a soluble ectodomain form that is generated by proteolytic processing of the former. The soluble form is constantly shed from the keratinocyte surface by TACE (TNF-α converting enzyme), a metalloproteinase of the ADAM family.8Franzke C.W. Tasanen K. Schäcke H. Zhou Z. Tryggvason K. Mauch C. Zigrino P. Sunnarborg S. Lee D.C. Fahrenholz F. Bruckner-Tuderman L. Transmembrane collagen XVII, an epithelial adhesion protein, is shed from the cell surface by ADAMs.EMBO J. 2002; 21: 5026-5035Crossref PubMed Scopus (188) Google Scholar Using short hairpin RNA (shRNA), the authors show that downregulation of type XVII collagen significantly blocks the proliferative and invasive capacity of several oral cancer cell lines in vitro and after transplantation in immune-compromised mice. This fits well with their observation that there is a positive correlation between the aggressiveness of human cancer samples and the level of staining of collagen type XVII. To further dissect the role of each of the post-cleavage subunits of type XVII collagen, the authors transfected expression vectors coding for either the endodomain or the exodomain into oral cancer cell lines. This allowed them to determine that the intracellular portion of collagen XVII favors cellular proliferation, whereas the extracellular portion drives tumor progression and invasion. The authors further show that forced expression of a non-cleavable collagen XVII acts as a dominant-negative mutant that prevents cancer progression. But more importantly, the authors found that antibodies that block the collagen XVII ectodomain also block cancer progression, thus providing the rationale for a new therapeutic strategy to target SCC progression. If these effects are reproduced in tumor xenografts, they could represent the first targeted therapy for advanced cutaneous SCC. Patients suffering from metastatic melanoma have benefited from targeted therapy, but even more so from the development of immunotherapy.5Luke J.J. Flaherty K.T. Ribas A. Long G.V. Targeted agents and immunotherapies: optimizing outcomes in melanoma.Nat. Rev. Clin. Oncol. 2017; 14: 463-482Crossref PubMed Scopus (737) Google Scholar This is not particularly surprising, given that this type of tumor harbors among the greatest number of mutations per DNA unit.9Chalmers Z.R. Connelly C.F. Fabrizio D. Gay L. Ali S.M. Ennis R. Schrock A. Campbell B. Shlien A. Chmielecki J. et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34Crossref PubMed Scopus (1805) Google Scholar These cancers, therefore, harbor a sufficient number of neo-antigens to allow immune editing once the immune system is de-repressed. BCC and SCC are two cancer types that globally present an even higher mutational load than melanoma.9Chalmers Z.R. Connelly C.F. Fabrizio D. Gay L. Ali S.M. Ennis R. Schrock A. Campbell B. Shlien A. Chmielecki J. et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34Crossref PubMed Scopus (1805) Google Scholar, 10Bonilla X. Parmentier L. King B. Bezrukov F. Kaya G. Zoete V. Seplyarskiy V.B. Sharpe H.J. McKee T. Letourneau A. et al.Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.Nat. Genet. 2016; 48: 398-406Crossref PubMed Scopus (285) Google Scholar It is therefore thought that immunotherapy could be a very promising tool to treat patients suffering from advanced/metastatic SCC. However, advanced, non-resectable SCC is most often observed in immune-compromised patients. In particular, organ transplant recipients too often require immunotherapy, but cannot benefit from it. Indeed, immunotherapy is associated with a very high rate of transplant failure, which prevents its use in lung and heart transplants.11Kittai A.S. Oldham H. Cetnar J. Taylor M. Immune Checkpoint Inhibitors in Organ Transplant Patients.J. Immunother. 2017; 40: 277-281Crossref PubMed Scopus (96) Google Scholar The possibility of undergoing dialysis allows renal transplant patients to choose to receive immunotherapy at the cost of their transplant, but, in our experience, they rarely choose this path. Hence, immunotherapy is not the golden bullet that we had hoped it would be for our advanced SCC patients. This context heightens the value of the work published by Galiger et al.,1Galiger C. Löffek S. Stemmler M.P. Kroeger J.K. Mittapalli V.R. Fauth L. Esser P.R. Kern J.S. Meiss F. Laßmann S. et al.Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression.Mol Ther. 2017; 26 (this issue): 17-30Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar as it suggests a novel therapeutic approach that should work in immune-compromised patients as well. Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma ProgressionGaliger et al.Molecular TherapySeptember 26, 2017In BriefGaliger et al. show that proteolytic shedding of the adhesion molecule collagen XVII is associated with squamous cell carcinoma invasion. Selective inhibition of shedding by monoclonal collagen XVII antibodies represses matrix-independent growth and invasiveness of squamous cell carcinoma cells and may offer a promising therapeutic strategy to prevent tumor progression. Full-Text PDF Open Archive