ARTICLE ADDENDUM Chimerism 5:3-4, 106--108; July–December 2014; © 2014 Taylor & Francis Group, LLC

Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer Valentina Cirello1,2 and Laura Fugazzola1,2,* 1

Endocrine Unit; Fondazione IRCCS Ca’ Granda; Milan, Italy; 2Department of Pathophysiology and Transplantation; University of Milan; Milan, Italy

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tudies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in other malignancies. Nevertheless, scanty data were available on the possible impact on the outcome of the disease. We demonstrated that FCM has a positive effect on thyroid cancer presentation and outcome. We also excluded that the better clinical features observed were due to the effect of pregnancy per se. In conclusion, FCM may have not only a protective role toward the onset of thyroid cancer, but also a positive effect on its progression. These findings give novel insights into the identification of the role of FCM in oncology and, consequently, in the potential therapeutic application of this physiological phenomenon.

Keywords: cancer protection, fetal microchimerism, pregnancy, thyroid cancer, women *Correspondence to: Laura Fugazzola, MD; Email: [email protected] Submitted: 09/30/2015 Revised: 10/05/2015 Accepted: 10/06/2015 http://dx.doi.org/10.1080/19381956.2015.1107254 Addendum to: Cirello V, Colombo C, Perrino M, De Leo S, Muzza M, Maffini MA, Fugazzola L. Fetal cell microchimerism in papillary thyroid cancer: A role in the outcome of the disease. Int J Cancer 2015; doi: 10.1002/ijc.29653. PMID:26105768

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Fetal cell microchimerism in neoplastic diseases A protective role for FCM has been favored in both solid and hematologic neoplastic diseases, based on the results obtained at either the tissue.1-5 or peripheral blood level.6-11 The presence of fetal cells with the ability to differentiate into the host phenotype has been demonstrated in several tissues (i.e. cervix, thyroid, breast), suggesting a role in the tissue repair.1,3,4 At the peripheral blood level, FCM has been primarily studied in relation to the risk to develop a given neoplasm, and it has been associated with a reduced risk in most cases. Indeed, consistent with the protective role favored at the tissue level, FCM was found to be significantly more prevalent in the peripheral blood of parous healthy Chimerism

controls than in women who developed breast, thyroid, and several solid malignancies.6-11 On the other hand, an alternative carcinogenetic role for FCM has been suggested in melanoma developed during pregnancy.12 and in colon cancer.9 Moreover, scanty and/or non-conclusive data exist on the correlation of FCM with the clinical outcome.6,8,13 Fetal cell microchimerism and thyroid cancer The data obtained by our group, both at the peripheral blood and the tissue level, indicated a favorable role for FCM in thyroid cancer.4,8,11 The immunophenotypic characterization of fetal cells detected in neoplastic tissues allowed to identify for some of them a possible role as natural killer cells, and for others an epithelial differentiation into follicular cells, suggesting a possible role in the attack to the tumor and in the tissue repair.4 In our pilot study performed at peripheral blood level, we demonstrated that the prevalence of circulating FCM was significantly higher in healthy parous control women than in those affected with thyroid cancer, indicating its protective role toward the onset of this neoplasm.8 Those data were in accordance with the results obtained in patients with breast cancer.6,9,10 or with other solid malignancies,7 suggesting that circulating microchimeric cells could participate in the protection against the onset of cancer. Moreover, in that study we observed a tendency toward a worst outcome in patients tested negative for FCM, but the number of cases limited the power of the statistical analyses.8 Similarly, women with breast cancer and adverse Volume 5 Issues 3-4

Figure 1. Possible roles of fetal microchimeric cell in thyroid cancer. At the thyroid tissue level, fetal cells might undergo a haematopoietic and epithelial differentiation with a role in the attack to the tumor and in the repair. At the peripheral blood level, fetal cells could have a cytotoxic role directed against pre-neoplastic cells (prevention of the tumor onset), and a sentinel function toward maternal malignant cells (suppression of tumor progression).

clinical features were found to have lower prevalence of circulating FCM, though without a statistical significance.6 Recently, we extended the research on the peripheral blood FCM in a larger series of women, and confirmed the previous data of a significantly higher frequency of circulating FCM in healthy parous women compared to those affected with thyroid cancer (63.6% vs 39.1%).11 The most interesting finding obtained in this larger series was that FMC-positive patients had a significantly better presentation at diagnosis than those FMC-negative, with a lower prevalence of cases with extrathyroidal extension (26.5 vs 50.9%, pD 0.027) and lymph node metastases (23.5 vs 45.3%, pD 0.044). Moreover, FMC-positive were found to be more frequently in remission than those FMC-negative (94.1 vs. 67.9%, pD 0.009), suggesting that FCM is also involved in the suppression of tumor progression.11 We also excluded that the beneficial effect observed might be due not to FCM, but to pregnancy itself. Indeed, considering only women tested negative for FCM, we

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observed that parous women showed more frequently an advanced stage of disease at diagnosis and lymph-nodal metastases compared to those nulliparous, indicating that the positive effect observed on tumor features was specifically related to FCM and not to pregnancy.11 Which roles for FCM in thyroid cancer The whole of the findings obtained, allows us to formulate an hypothesis on the role of FCM in thyroid cancer, as summarized in the Figure 1. The higher prevalence of circulating fetal cells in healthy parous women, with respect to patients with thyroid cancer, might indicate that activated fetal microchimeric immune cells could play a cancer surveillance function, as already proposed for breast cancer.14 Circulating fetal cells are likely to derive from progenitors or stemlike cells localized not only within the thyroid gland. Indeed, if fetal microchimeric cells resided only within the thyroid, we would expect them to disappear from the circulation after thyroidectomy. Still, no

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differences in the interval between thyroidectomy and enrollment among patients tested positive or negative for FMC were observed,11 suggesting that fetal cells also reside within bone marrow niches, as previously reported.15 Through the circulation, fetal cells are believed to migrate to affected tissues, where they differentiate into epithelial, haematopoietic , stromal or endothelial cells, as demonstrated by their immunophenotypic characterization in humans.1,3,4,12 and in animal model studies.16,17 In thyroid cancer, we found fetal cells with a differentiation consistent with NK cells and thus a possible role in the attack to neoplastic cells was hypothesized. We also demonstrated fetal cells with an epithelial differentiation interposed between maternal cells to form follicles, indicating a role in tissue repair.4 In our recent study, we showed an additional possible function for fetal microchimeric cells. Immune-active fetal cells could not only act and/or cooperate with maternal immune cells in the immune surveillance against tumor,6,8 but also perform a “sentinel function” after the removal of the tumor tissue, as indicated by the significant better outcome observed in FCM-positive patients.11 Nevertheless, additional studies are required to identify the specific mechanisms by which circulating fetal cells could participate in the protection toward or in the suppression of cancers.

Conclusion We demonstrated for the first time that circulating FCM may have a protective role toward the onset and the progression of thyroid cancer. Fetal microchimeric cells are more frequently observed in healthy parous women than in those affected with papillary thyroid cancer and a significantly lower extrathyroidal extension and a good prognosis of the tumor is reported in patients harboring FCM. As a possible clinical impact of this finding, the testing for FMC could be used, in parous women with thyroid cancer, to precociously identify high risk tumors to be submitted to a more aggressive initial treatment.

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Disclosure of Potential Conflicts of Interest

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6. Gadi VK, Malone KE, Guthrie KA, Porter PL, Nelson JL. Case-control study of fetal microchimerism and breast cancer. PLoS One 2008; 3:e1706; PMID:18320027; http://dx.doi.org/10.1371/journal. pone.0001706 7. Gilmore GL, Haq B, Shadduck RK, Jasthy SL, Lister J. Fetal–maternal microchimerism in normal parous females and parous female cancer patients. Exp Hematol 2008; 36:1073-7; PMID:18508187; http://dx.doi. org/10.1016/j.exphem.2008.03.020 8. Cirello V, Perrino M, Colombo C, Muzza M, Filopanti M, Vicentini L, Beck-peccoz P, Fugazzola L. Fetal cell microchimerism in papillary thyroid cancer: studies in peripheral blood and tissues. Int J Cancer 2010; 126:2874-8; PMID:19856309 9. Kamper-Jørgensen M, Biggar RJ, Tjønneland A, Hjalgrim H, Kroman N, Rostgaard K, Stamper CL, Olsen A, Andersen AM, Gadi VK. Opposite effects of microchimerism on breast and colon cancer. Eur J Cancer 2012; 48:2227-35; PMID:22397765; http://dx.doi. org/10.1016/j.ejca.2012.02.006 10. Eun JK, Guthrie KA, Zirpoli G, Gadi VK. In situ breast cancer and microchimerism. Sci Rep 2013; 3:2192; PMID:23846681; http://dx.doi.org/10.1038/ srep02192 11. Cirello V, Colombo C, Perrino M, De Leo S, Muzza M, Maffini MA, Fugazzola L. Fetal cell microchimerism in papillary thyroid cancer: A role in the outcome of the disease. Int J Cancer 2015 Jun 23; 137(34):2989-93 12. Nguyen Huu S, Oster M, Avril MF, Boitier F, Mortier L, Richard MA, Kerob D, Maubec E, Sou-

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Volume 5 Issues 3-4

Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer.

Studies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in othe...
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