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A recent review article in International Journal of Cancer underlined the role of tissue microenvironment in developmental regulation of tumor cells and showed that modifications of the stroma may revert tumor cells to a normal phenotype.1 We present preliminary data suggesting that Down's Syndrome (DS) could be a natural model of cancer protection due to a particular cell microenvironment. An epidemiological study dealing with breast cancer in subjects with DS2 and reports on cancer incidence3, 4, 5 and death rates6, 7 in DS subjects have clearly showed a strikingly lower rate of breast neoplasms among DS subjects in comparison to non-DS subjects. If we consider the considerable increase in life expectancy among the DS population over the past 5 decades, breast neoplasms are estimated to be 10–25 times less frequent in DS subjects than in the general population.2, 7 This makes DS, which is caused by a constitutional supernumerary chromosome 21 (trisomy 21),8 the most powerful natural condition that offers protection against the most common malignant neoplasm in women, breast cancer. It is surprising that a genetic impairment may have such a favourable effect, but we believe that it deserves our undivided attention. From a broader oncological perspective, neoplasms in DS subjects have a very particular distribution pattern in comparison to those in the general population; this pattern is what we refer to as the "Down Syndrome tumour profile."9 In DS subjects, some neoplasms are considerably or moderately over-represented, some are represented at a similar frequency, whereas others are slightly or markedly under-represented, when compared to the non-DS population. One could therefore assume that the theoretical 1.5-fold overexpression of genes on chromosome 21 that characterises the DS condition has different positive, neutral and negative effects on tumour onset and progression, depending on the original tissue. Chromosome 21 is the smallest of our chromosomes, harbouring nearly 250 genes, which is just 1% of the human genome.10 It is probable that some of the overexpressed genes resulting from the gene dosage effect and residing on the supernumerary chromosome 21 could have a protective or favourable effect on various tumour cells. To date, however, no single gene has been isolated to explain oncogenic events in DS. Another cause could be an epigenetic process at work due to the host microenvironment in persons with DS. On examining the features common to neoplasms that are rare or lacking in DS subjects, we were forced to seriously consider the role played by stroma. The stroma of a solid epithelial tumour consists of a population of non-malignant tumour cells including fibroblasts, and a main cell component, which produces the fibroblast extracellular matrix (ECM) surrounding the malignant cells. It is well established that the stroma plays a key role in malignant epithelial tumour homeostasis and development,11 and it is particularly interesting that the most common malignancy in DS children and adults is leukaemia, which is devoid of stroma. Germ cell tumours, lymphomas, sarcomas and retinoblastomas,3, 6, 12 which are all renowned for their very poorly developed stroma, are also more common in DS subjects. Conversely, cancers of the breast, digestive tract, head and neck, bronchus and skin, which are very rare in adults with DS,3, 7, 9 are neoplasms that are sustained by well-developed stroma. In the absence of an as yet conclusive explanation for this protective effect against cancer, it is worth considering the hypothesis that the stroma plays an important role in inhibiting solid tumours, and particularly breast cancer. Fibroblasts may promote the development of cancer, and many studies indicate that cancer cells change their microenvironment by modifying fibroblasts and their related extra cellular matrix (ECM).11, 13, 14 Moreover, fibroblasts taken from distal non-tumorigenic sites in patients with a hereditary predisposition to cancer in different sites, including the breast, present altered phenotypes that favour tumour development.14 Conversely, it would be interesting to investigate if DS fibroblasts have an inhibitory effect on the development of breast cancer in DS subjects. If this hypothesis were valid, we could consider that trisomic 21 fibroblasts and their related ECM offer more resistance to cancer development than euploid fibroblasts and their related matrix. In our studies, neither the in vitro co-culturing of a breast cancer cell line and fibroblasts from a patient with DS or in vivo xenografts on nude mice of both cell lines resulted in the inhibition of breast cancer cell growth. In contrast, when cultured onto an ECM (Fig. 1) secreted by confluent DS fibroblasts, the same breast cancer cell line showed significant growth inhibition (30%) compared to a matrix produced by confluent euploid fibroblasts (Fig. 2). The ECM was not fully secreted during the in vivo experiments (it needs 10 days to be secreted by confluent fibroblasts in vitro), which leads us to suggest that tumour formation may, in fact, be inhibited by one or more ECM components. Network structure of DS fibroblast ECM. When the DS fibroblast culture reached confluence, the cells were lysed by osmotic shock and the ECM was washed extensively and further distinguished by an anti-vimentin antibody (Biogenex MA74-5C). In vitro inhibitory growth effect of breast cancer proliferation by DS fibroblast ECM (experiments in duplicate). Human breast cancer MDA-MB431 cells were cultured in RPMI 1640-fetal calf serum onto the ECM of the euploid human fibroblasts HS 27 and 21 trisomic human fibroblasts DE 532. The ECM were prepared once the primary cultures of newborn fibroblasts had reached confluence. Breast cancer cells were counted and distinguished by the anticytokeratin 7 antibody (DAKO NP 034, Copenhagen, Denmark). Further experiments are needed to understand the inhibitory effect of DS-ECM components on malignant breast cancer cell growth, particularly at early stages of tumorigenesis, i.e., at the stage between immortalisation and malignancy. Such an approach, however, will require very sophisticated experiments to validate the constitutional microenvironment hypothesis and this remains far from becoming a reality. It would also be interesting to study the effect of DS-ECM components on the conversion of breast epithelial cells at a very early phase of the onset of the breast tumour. Nonetheless, this is the first experimental observation of a natural resistance to cancer proliferation mediated through proteins or another component (or components) secreted by the ECM of a connective tissue. The genetic imbalance of trisomy 21 results from complex interactions of chromosome 21 overexpressed genes. Trisomy 21 fibroblasts have migration anomalies due to abnormal cell adhesivity and membrane fluidity anomalies.15, 16 Differences in the composition of connective tissue ECM have also been reported both in utero and after birth, particularly for Types I, II, V and VI collagen, for hyaluronan and for Type II interstitial metalloprotease.17, 18 These differences have been linked to the genes Col 6A1, Beta 2 integrin receptor, SOD2 and IFN gamma that map to chromosome 21. It has been underlined recently that endostatin, which is encoded by the gene Col 18A1, which in turn maps to chromosome 21 and is the most powerful inhibitor of tumour angiogenesis, is significantly higher in the serum of subjects with DS.19 This could indicate that altered angiogenesis is responsible for the lower incidence of solid tumours in DS subjects. Our data is complementary and supports the hypothesis that the non-vascular component of the connective tissue could also play an inhibitory role by interacting with neoplastic cells. Our hypothesis and the preliminary data presented here suggest that the antitumoral effect of the fibroblast ECM in DS is efficient at a very early stage, well before the onset of the angiogenesis process. This may well explain why stroma-rich tumours that occur in the non-DS population are very rarely found in DS patients. The recent observation of tumour reversion after microenvironment modification coincides with this theory.1 We can therefore conclude that the study of connective tissue and tumour stroma in DS subjects could shed great light on our understanding of the resistance these persons display to many solid tumours and particularly breast cancer. Yours sincerely, This article was edited by English Booster Ltd. Jean Bénard, Nadine Béron-Gaillard, Daniel Satgé