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CD10 is a cell surface zinc-dependent metallo-endoprotease which cleaves signalling peptides. Its expression can be found in different hematopoietic cell types, but also in a wide variety of non-lymphoid cells and neoplastic tissues, thus being of help for pathological diagnosis. The stromal expression of CD10 in several solid tumours, such as gastric, colorectal or breast tumours is correlated with invasiveness, metastatic potential and poor prognosis. CD10 has also been found of use for stem cells isolation in various tissues and is relevant for the maintenance of the mammary stem niche. In this paper we review the molecular anatomy of CD10.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases characterized by the ability to degrade extracellular matrix proteins.1,2 Their normal activity, under tight regulation of endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs), is to maintain tissue homeostasis, participating in normal development, angiogenesis and wound repair by initiating inflammatory, cardiovascular, and neurogenic responses.3,4 The elevated levels of distinct MMPs found in tumour tissues cause tissue dissolution and make tumour cells able of invasion and metastasis. 1,5
Stromal cells, but not carcinoma cells, produce MMPs in tumours, being stimulated by cytokines and metalloproteinase inducers.6 MMPs also have a role in tumour angiogenesis by cleaving plasminogen and producing the angiogenesis inhibitor angiostatin.6
CD10, also called neutral endopeptidase (NEP), metallo-endopeptidase EC 3.4.24.11, enkephalinase, neprilysin, or common acute lymphoblastic leukemia antigen (CALLA), is a 90-110 kDa cell surface zinc-dependent metalloproteinase.7,8 The CD10-related DNA sequences are found on human chromosome 3, at 3q21-27 locus.9
CD 10 expression in normal vs. tumoral tissue
CD10 is expressed by different hematopoietic cell types as well as in immature B lymphocytes, 10,11 but also in a wide variety of non-lymphoid cells and neoplastic tissues.12
The CD10 antigen is expressed in germinal centre cells, in acute lymphoblastic leukaemia, follicle centre cell lymphoma and is considered as a marker of centrofollicular-derived diffuse large B-cell lymphomas.13-15
In salivary glands only fibrocytes within the intralobular stroma express CD10, the normal myoepithelial cells being negative. CD10 expression in neoplastic myoepithelial cells was equally found in benign and malignant neoplasms.16
CD10 positively labels normal, ectopic, and neoplastic endometrial stromal cells17,18 but there was found no expression of CD10 in myometrium, endometrial and cervical glands, cervical squamous epithelia, or tubal epithelia and stroma.19
The cervical mesonephric remnants are CD10 positive20 and also intratubular germ cell neoplasia, the precursors of testicular germ cell tumours and seminomas express CD10.21
There was found no expression of CD10 in normal thyroid tissue, benign lesions and pure papillary carcinomas. In contrast, CD10 was expressed in follicular carcinomas and follicular variant of papillary thyroid carcinomas.22
CD10 is useful in distinguishing trichoepithelioma from basal cell carcinoma (BCC) as wells as basal cell carcinoma from squamous cell carcinoma (SCC); if tumour cells express CD10, this would favour a BCC diagnosis. 23,24
A strong expression of CD10 has been observed in clear cell and papillary renal cell carcinomas, but CD10 expression lacks in chromophobe renal cell carcinomas.25,26
Table. Known tissue expression for CD10; "?” indicates unknown possibility
CD 10 in breast and breast cancer
Mammary gland epithelium is composed of two compartments: the epithelial compartment, composed of the inner layer of secretory cells and the outer layer of myoepithelial cells bordering the basal lamina which separates the epithelial compartment from the extracellular matrix.37 CD10 has a major role in breast morphogenesis and in adult tissue it stains the myoepithelial layer of normal ducts38 (Figure). We also found (personal unpublished results) that CD10 labels periepithelial spindle-shaped mammary stromal cells (Figure).
The progesterone receptor is expressed in a subset of CD10-positive basal cells and progesterone stimulates this CD10-positive cell compartment, which is enriched for bipotent progenitor activity.39 In mammary epithelium CD10 is not only a cell surface marker but also acts as a functional regulator of normal mammary progenitor cells by maintaining stem cells/early progenitors and by regulating their conversion to luminal progenitors.40
CD10 also labels myoepithelial cells in intraductal papilloma, adenosis, fibroadenoma, phyllodes tumour, ductal hyperplasia and in situ carcinoma, being of help in confuse breast lesions.33CD 10 seems to be implicated in the remodelling and the involution of mammary gland through retinoic acid, a signaling molecule which modulates the expression of matrix metalloproteinases (MMPs).43,44
There is evidence that in normal breast tissue some fibroblastoid stromal cells are also highlighted by CD10,33 but there are studies in which CD10 expression in such cells was not assessed.8
New data suggest that the tumour microenvironment is very important in cancer progression and stromal changes could be very important in breast ductal carcinoma in situ (DCIS) progression to invasive cancer.45
One of the stromal changes at the invasion site in breast tumour is the appearance of myofibroblasts from fibroblasts, mediated by tumoral secreted cytokines like TGF beta,8 and characterized by the loss of CD34 expression and acquisition of alpha-SMA expression.46
CD10 proteolytic activity may suggest that its expression in a tumour is associated with increased invasive and metastatic potential.8
Stromal expression of CD10 was found to be increased in invasive breast cancers, as compared to non-invasive breast cancers.8,47 Stromal expression of CD10 in invasive ductal carcinoma has been significantly correlated with increasing tumour size, increasing histologic grade, the presence of nodal metastases, estrogen receptor negative status, HER-2/NEU overexpression and decreased survival.8,47-49
There are data which sustain the fact that neo-adjuvant anthracycline-based chemother-apy can modify stromal CD10 expression in breast cancer. An increase in CD10 expression after 3 cycles of chemotherapy appears to correlate with poor clinical response.50
These results suggest that stromal expression of CD10 in breast cancer can be an important prognostic factor and target for development of novel therapies.48,49
CD10 and stem cells
Stem cells maintain the tissue structure and homeostasis.51
CD10 labels the surface of stem cells in several normal adult human tissues like bone marrow, adipose tissue, dental pulp, skin, placenta and lung42,52-54 or in thymus tissue from stillborn children.53 Specificity of CD10 for mesenchymal stem cells should be regarded with caution as the diagnosis of mesenchymal stem, or stromal, cells is an in vitro one55 and so, the molecular phenotypes of in situ cells could differ to cultured cells. For example, cultured adult dental stem cells were found negative for CD10 expression.56
CD10 and CD92 are potential markers of osteogenic and adipogenic differentiation of human bone marrow mesenchymal stromal cells,57 CD10 being correlated with a high clonogenic potential of these cells.58 The expression of CD10, as well as of CD200, in fat depots, is depot-dependent and associates with adipogenic capacities.59
Expression of CD10 was also found in embryonic tissues, such as cartilage and kidney.60,61 In human foetuses, CD10 is expressed in epithelia, such as hair follicles, mammary epithelium, urinary and intestinal epithelia, as well as in fibrous tissues surrounding lower airways and lung alveoli, in the periosteum and ossification center, and in the glans of external genitalia, but not in vascular progenitor cells.10
There are conflicting reports about the expression of CD10 on mesenchymal stem cells, a heterogeneous population of adult multipotent cells that can be found in various human tissues, able of regenerating mesenchymal tissues. Gronthos et al. sustained that these cells are CD10 positive, but other researchers found such cells being CD10 negative.62,63
CD10 is also a marker for breast epithelial stem cells, early and bipotent progenitors, and later myoepithelial lineage cells and, used together with the epithelial cell adhesion molecule, can help to discriminate basal from luminal breast epithelial subpopulations.40
Recent studies have demonstrated that the protease activity of CD10 maintains the undifferentiated progenitor population in the human mammary lineage inhibiting their transformation in mature progenitors, luminal or myoepithelial.64
The expression of CD10 in head and neck squamous cell carcinoma is associated with cancer stem cell-like phenotype and was correlated with treatment failure.65 This indicates, as much more existing evidence, that the cancer stem cell hypothesis could indeed be of value when considering the pathogeny or spread of cancer.66
In conclusion, the expression of CD10 in various tissues and conditions should be regarded carefully and must be specifically related to the normal or pathological status of the tissue. Inclusion of CD10 in specific panels of markers can avoid misdiagnoses.
1. Merdad A, Karim S, Schulten HJ, et al. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res 2014;34:1355-66.
2. Johansson N, Ahonen M, Kahari VM. Matrix metalloproteinases in tumor invasion. Cell Mol Life Sci 2000;57:5-15. [CrossRef]
3. Hiller O, Lichte A, Oberpichler A, Kocourek A, Tschesche H. Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII. J Biol Chem 2000;275:33008-13. [CrossRef]
4. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 2006;11:1696-701. [CrossRef]
5. Kohrmann A, Kammerer U, Kapp M, Dietl J, Anacker J. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 2009;9:188. [CrossRef]
6. Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 2000;19:6642-50. [CrossRef]
7. Thong A, Muller D, Feuerstacke C, Mietens A, Stammler A, Middendorff R. Neutral endopeptidase (CD10) is abundantly expressed in the epididymis and localized to a distinct population of epithelial cells--its relevance for CNP degradation. Mol Cell Endocrinol 2014;382:234-43. [CrossRef]
8. Taghizadeh-Kermani A, Jafarian AH, Ashabyamin R, et al. The Stromal Overexpression of CD10 in Invasive Breast Cancer and its Association with Clincophathologic Factors. Iran J Cancer Prev 2014;7:17-21.
9. Barker PE, Shipp MA, D'Adamio L, Masteller EL, Reinherz EL. The common acute lymphoblastic leukemia antigen gene maps to chromosomal region 3 (q21-q27). J Immunol 1989;142:283-7.
10. Kim JH, Hwang SE, Yu HC, et al. Distribution of CD10-positive epithelial and mesenchymal cells in human mid-term fetuses: a comparison with CD34 expression. Anat Cell Biol 2014;47:28-39. [CrossRef]
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