The DCIS to IDC transition is a clinically important, yet poorly understood, step in breast tumorigenesis. The importance of changes in the microenvironment during tumor progression has been increasingly recognized 
. CD34 is a transmembrane glycoprotein expressed by hematopoietic stem cells, endothelial cells and mesenchymal cells in different tissues, including breast tissue, and is thought to be involved in the modulation of cell adhesion and signal transduction. They constitute a population of stromal cells that are capable of synthetizing connective tissue matrix. Moreover, CD34 fibrocytes are potent antigen-presenting cells and they may play a role in host response to tissue damage 
. However, their histogenesis and function have not yet been elucidated. Some authors have suggested that CD34 fibrocytes in breast lesions are recruited via the bloodstream and invade sites of tissue damage 
. We believe that the CD34 fibrocytes altered (transformed into SMA myofibroblasts) by tissue damage are fibrocytes already present in stroma (in a constitutional manner) before the onset of lesions, and no recruitment of CD34 fibrocytes from the blood occurs, at least in breast tissue. This hypothesis relies on the facts that CD34 stromal cells are already present from the 10th
week of gestation and that there is strong expression of CD34 fibrocytes in the normal breast. This distribution of CD34 fibrocytes is similar to that of normal skin, and we know that the mammary gland develops from solid epithelial cords growing from the epidermal layer into the underlying mesenchyme 
, and therefore has the same embryological characteristics as normal skin.
Several studies have shown the loss of CD34 fibrocytes to be a feature of stromal alterations associated with invasive carcinomas of the breast 
(). This is underlined by the findings of the present study. Invasive carcinomas revealed complete loss of stromal CD34 fibrocytes in 100% of cases. Loss of CD34 expression was accompanied by acquisition of SMA expression, with only a few exceptions. These data indicate a strong negative association between the presence of CD34 fibrocytes and the malignancy of ductal breast lesions. However, the stroma surrounding ductal carcinoma in situ was also characterized by loss of CD34 fibrocytes. Indeed, we found a decrease in CD34 expression in DCIS lesions compared with normal breast tissue. This loss of expression had a stronger effect when the grade of DCIS was higher. These results were in accordance with those of Chauhan et al. 
. Furthermore, this decrease in CD34 expression was inversely correlated with a progressive increase in the expression of SMA around foci of DCIS. To our knowledge, this is the first time that a statistically significant difference in the expression of SMA in relation to DCIS grade has been demonstrated. Similarly, this is one of the first studies to demonstrate a statistically significant relationship between the necrosis associated with in situ lesions and immunohistochemical stromal expression of CD34. Indeed, several studies have shown that comedonecrosis on core biopsy is significantly associated with invasion 
. The various factors secreted during necrosis could decrease the expression of CD34 stroma, facilitating tumor invasion. Therefore, modulation of the expression of CD34 could be one explanation of the role of necrosis in tumor invasion.
Expression of CD34 fibrocytes and SMA myofibroblasts in DCIS and IDC: literature review.
However, the mechanism leading to the loss of CD34 fibrocytes in the stroma of carcinomas are far from being understood. Breast cancer cells have been shown to be capable of factor secretion 
. Therefore, we speculate that loss of CD34 fibrocytes and gain of SMA myofibroblasts might be initiated by a soluble factor secreted by DCIS cells. It has been shown that medium conditioned with breast cancer cell line MCF-7 induces SMA expression in stromal cells obtained from normal breast tissue 
. Moreover, some research has found that CD34 fibrocytes acquire SMA expression when exposed to transforming growth factor-β 
. Considering the results of the present study, it appears to be more likely that CD34 fibrocytes acquire SMA expression and in turn down-regulate CD34 expression.
We believe that several mechanisms may explain the promotion of tumor invasion that induces the transformation of CD34 fibrocytes to SMA myofibroblasts. First, CD34 fibrocytes are potent antigen-presenting cells capable of priming naïve T-cells, and might be involved in specific immune surveillance 
. A subpopulation of CD34 fibrocytes expresses MHC II molecules and CD80 
. Second, CD34 fibrocytes are involved in the remodeling of stromal tissue damage not only via tissue contractility via TGF-beta, collagen I and III synthesis and SMA, but also in terms of migration factors within the injured tissue via CCR7, CXCR4, SLC, and CXCL12. Third, CD34 fibrocytes also play a role in angiogenesis via bFGF, VEGF, PDGF-a, IL-8, and MMP-9. The stromal reaction induced by carcinomatous lesions leads to acquisition of SMA expression and in turn to stabilization of the lesion (wound contraction) that helps prevent the spread of tissue damage 
. This may reflect a defense mechanism against “stromal invasion” that induces a phenomenon of stromal healing and stabilization. However, the phenotypic transformation of CD34 fibrocytes into SMA myofibroblasts could also cause the loss of most essential functions (including immunity, cell adhesion, motility, stromal remodeling, and angiogenesis inhibition), and in a paradoxical manner promote tumorigenesis, thus facilitating invasion and metastatic dissemination of tumor cells. Our study has shown that fibroblast CD34 expression is consistently lost in invasive breast carcinomas, and in a high proportion of cases of DCIS, particularly necrotic and/or high-grade lesions, which are thought to be more likely to progress to invasion 
. Moreover, the change in CD34 expression is very localized, with loss around ducts containing DCIS, but retained expression around adjacent normal breast glands 
. This raises the possibility that loss of CD34 may be related to invasive potential at least in ductal lesions. Indeed, in invasive lobular carcinoma that tend not to be associated with an altered stroma, our preliminary observations do not confirm so obviously the stromal loss of CD34 and acquisition of SMA (unpublished data).
Therefore, future research on both CD34 fibrocytes and mechanisms stromal changes are essential in the future and may potentially lead to new treatment approaches. Such studies are now in progress.