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Skin wounds trigger tumors

Researchers show how stem cells in hair follicles can transform into cancer while helping to heal an injury

By | February 14, 2011

Even small wounds like paper cuts can activate cancer-provoking genes in the skin as it heals, leading to an increased risk of the most commonly diagnosed cancer, according to a study published online today (February 14) in the Proceedings of the National Academy of Sciences.
Inactive stem cells (green) reside at the bottom of hair follicles but can be recruited to a wound site to help with the healing process.
Image: Jeremy Reiter and Sonny Wong, UCSF
The work is "pioneering," said Ervin Epstein, a cancer researcher at the Children's Hospital Oakland Research Institute in California, who was not involved in the research. "What could be more important than identifying the cell of origin of the most common of human cancers?" Basal cell carcinoma is a type of skin cancer that frequently arises from the cells of hair follicles, which contain stem cells that differentiate and divide to replace the hair after it falls out. If these follicular cells accumulate errors in the DNA that regulates their division, they can spawn tumorous growth. Although the follicular stem cells function mainly in hair growth, injuries to the surrounding skin can recruit these stem cells to aid in the healing process. Given that various types of injuries, from surgical incisions to stomach ulcers, have been linked to cancer, Jeremy Reiter, a biochemist at the University of California, San Francisco, and his postdoc Sunny Wong hypothesized that skin wounds may promote basal cell carcinoma. Reiter and Wong to took skin biopsies of laboratory mice to induce topical injuries. As the stem cells from the hair follicles migrated to the wound site to help heal the injury, Reiter and Wong found that the cells expressed high levels of the oncogenes commonly found in basal cell carcinomas. Sure enough, after 10 weeks, the researchers saw the formation of basal cell carcinoma-like tumors in the injured mice, suggesting that this type of skin cancer could be triggered by an injury and subsequent migration of follicular stem cells. "It's been well-known that the skin mobilizes cells from the hair follicles" to heal injuries, Epstein said. "What Wong and Reiter showed is that if you mobilize these cells into the epidermis, they can produce tumors." Reiter said that over the past 10 years, more and more scientists have begun to think that "cancers are wounds gone awry." Normally, the hair follicle represses the tumor-generating potential of the stem cells, he said, "but when these cells leave their niche, the reins that are supplied by the [follicle] come off. " The development of basal cell carcinomas wasn't limited to relatively major wounds like skin biopsy. Even small incisions could induce carcinomas, the researchers found. But Reiter cautions that these results aren't a cause to panic over every single paper cut. Although basal cell carcinomas may originate from improper wound healing, Reiter said, only a tiny fraction of injuries ever generate cancer. "These results give us an understanding of how the normal healing process can become co-opted to promote tumors," Reiter said. S.Y. Wong and J.F. Reiter, "Wounding mobilizes hair follicle stem cells to form tumors," PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1013098108, 2011.
**__Related stories:__***linkurl:Equations that Spell Disaster;http://www.the-scientist.com/2010/12/1/40/1/
[December 2010]*linkurl:Gene + virus + injury = disease?;http://www.the-scientist.com/blog/display/57509/
[24th June 2010]*linkurl:Related F1000 evaluations;http://f1000.com/search/all?query=basal+cell+carcinoma
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Comments

Avatar of: Mike Waldrep

Mike Waldrep

Posts: 155

February 15, 2011

Interesting! I hope that everyone had a great Valentine's Day!

February 15, 2011

Very interesting observation indeed! Who could have thought that tiny wounds like paper cuts can also lead to traumatic consequences like tumor formation? Thanks for sharing.
Avatar of: Rich patrock

Rich patrock

Posts: 7

February 15, 2011

My good friend published a paper a couple years back discussing the importance of this concept to treatment. The article is found at:\n\nhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678149/\n\nI am glad his insights are getting broader support.\n\nWilliam W Harless\nBMC Cancer. 2009; 9: 118.\nPublished online 2009 April 22. doi: 10.1186/1471-2407-9-118.\nRevisiting perioperative chemotherapy: the critical importance of targeting residual cancer prior to wound healing\nWilliam W Harless
Avatar of: Jonas Moses

Jonas Moses

Posts: 26

February 15, 2011

While I tend to agree with the assessment that cancers can be thought of as "wounds gone awry," and that there is a likely connection between wounds (even surgical wounds) and the occurrence of tumors, I think the article makes a huge leap to assume that this has something to do with oncogenes.\n\nTime and again the oncogene theory has been shown to be rife with holes. This is a worn-out theory and desperately needs to be revisited. No less than Peter Duesberg, in a 2009 conversation we shared, agreed with me that changes in micro-environment play a far more dominant role in cancer development. \n\nI would propose that physical insult to tissues - in this case, epidermal wounds - most certainly impact the cellular micro-environment. From the initial incursion of microbes and surface toxins into the wound, and the exposure of the dermis to atmosphere (and resultant oxidation) to the inflammatory response, there are potentially ample, induced changes in micro-environment that may cause cells to begin transformation. Once one cell transforms and successfully begins secreting tumor ECM, the effect is domino-like. \n\nUnchecked by a healthy/functional immune system, a tumor ensues. Oversimplification, yes...but, I submit, illustrative of a reasonable alternative to the oncogene theory.\n\nRespectfully, \n\nDr. Jonas Moses\n\n
Avatar of: James Wilmer

James Wilmer

Posts: 18

February 15, 2011

The Carcinogenesis group at the NIEHS was doing similar work back in the 1990's, and, as I recall, Laurie Hansen and Ray Tennant (and probably other co-authors as well) reported that the skin cells that were transformed by chemical carcinogens arose from hair follicles. Also in the mid-1990's Mike Luster's Environmental Immunology group at the NIEHS showed that tumor promoters and chemical carcinogens were capable of inducing proinflammatory cytokines and chemokines in normal human epidermal keratinocytes.
Avatar of: Hugh Fletcher

Hugh Fletcher

Posts: 44

February 16, 2011

This research was performed: "in a mouse model conditionally expressing GLI1 and in a model with homozygous inactivation of Ptch1, mimicking the situation in human BCCs". The mouse was predisposed to basal cell carcinoma by two mutations. Oncogenes promote cell division and migration, both required for wound healing, which is what oncogenes are for, and for cancer. The problem comes when they don't switch off afterwards,and experience shows that to be vanishingly rare. Infection is a much bigger risk. \nWhat worries me much more is the idea of a biopsy to get a sample of a potential tumour. A needle biopsy being withdrawn would presumably leave a trail of potentially cancerous cells along the wound environment caused by the needle from the interior of the "lump" to the patient's epidermis. It would at least leave a wound environment from the healthy exterior to the suspect interior of the lump. Has anyone asked whether a biopsy harms the future prognosis for the patient?
Avatar of: Gar Hildenbrand

Gar Hildenbrand

Posts: 5

February 18, 2011

Bill Coley and Norm Higinbotham published data in 1933 that was systematically collected over Coley's long tenure as chief of Memorial's bone ward. The paper, "Injury as a causative factor in the development of tumors" is posted here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1390454/pdf/annsurg00573-0032.pdf?tool=pmcentrez\nCancer regressions induced by Coley's sterile vaccine of S pyogenes + S marcescens led Lloyd Old to dub him the "Father of Tumor Immunotherapy." Coley has been dead for 75 years, but we may, at long last, be catching up to his insights.

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