Abstract
We have previously shown the existence of ICLC in human resting mammary gland stroma by means of methylene blue (vital) staining and c‐kit immunopositivity (immunofluorescence and immunohistochemistry). In addition, we reported the phenotype characteristics of these ICLC in vitro (primary cell cultures). Since the identification of ICLC outside the gut requires, at this moment, the obligatory use of TEM, we used this technique and provide unequivocal evidence for the presence of ICLC in the intralobular stroma of human resting mammary gland.
According to the‘platinum standard’ (10 TEM criteria for the certitude diagnosis of ICLC), we found interstitial cells with the following characteristics: 1. location: among the tubulo‐alveolar structures, in the non‐epithelial space; 2. caveolae:˜2.5% of cell volume; 3. mitochondria:˜10% of cell volume; 4. endoplasmic reticulum: either smooth or rough, ˜2–3% of cell volume; 5. cytoskeleton: intermediate and thin filaments, as well as microtubules are present; 6.myosin thick filaments: undetectable; 7. basal lamina: occasionally found; 8. gap junctions: occasionally found; 9. close contacts with targets: nerve fibers, capillaries, immunoreactive cells by ‘stromal synapses’; 10. characteristic cytoplasmic processes: i) number: frequently 2–3; ii) lenght: several tens of ˜m; iii) thickness: uneven caliber, 0.1–0.5 ˜m, with dilations, but very thin from the emerging point; iv) aspect: moniliform, usually with mitochondria located in dilations; y) branching: dichotomous pattern; vi) Ca2+ release units: are present; vii) network labyrinthic system: overlapping cytoplasmic processes.
It remains to be established which of the possible roles that we previously suggested for ICLC (e.g. juxta‐ and/or paracrine secretion, uncommited progenitor cells, immunological surveillance, intercellular signaling, etc.) are essential for the epithelium/stroma equilibrium in the mammary gland under normal or pathological conditions.
Keywords: interstitial Cajal‐like cells, human mammary gland, stromal cells, stromal synapses, immune synapses, caveolae, cell processes, fibroblasts, intercellular communications, electron microscopy
References
- 1. Faussone‐Pellegrini, MS . Interstitial cells of Cajal: once negligible players, now blazing protagonists. It J Anat Embryol. 2005; 110: 11–31. [PubMed] [Google Scholar]
- 2. Sanders, KM , Koh, SD , Ward, SM . Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol. 2006; 68: 17.1–17.37. [DOI] [PubMed] [Google Scholar]
- 3. D'Amato, G , Steinert, DM , McAuliffe, JC , Trent, JC . Update on the biology and therapy of gastrointestinal stromal tumors. Cancer Control. 2005; 12: 44–56. [DOI] [PubMed] [Google Scholar]
- 4. Candelaria, M , de la Garza, J , Duenas‐Gonzalez, A . A clinical and biological overview of gastrointestinal stromal tumors. Med Oncol. 2005; 22: 1–10. [DOI] [PubMed] [Google Scholar]
- 5. Huizinga, JD , Faussone‐Pellegrini, MS . About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract. J Cell Mol Med. 2005; 9: 468–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Harhun, MI , Pucovsky, V , Povstyan, OV , Gordienko, DV , Bolton, TB . Interstitial cells in the vasculature. J Cell Mol Med. 2005; 9: 232–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Lang, RJ , Klemm, MF . Interstitial cell of Cajal‐like cells in the upper urinary tract. J Cell Mol Med. 2005; 9: 543–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Popescu, LM , Hinescu, ME , Ionescu, N , Ciontea, SM , Cretoiu, D , Ardelean, C . Interstitial cells of Cajal in pancreas. J Cell Mol Med. 2005; 9: 169–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Popescu, LM , Hinescu, ME , Radu, E , Ciontea, SM , Cretoiu, D , Leabu, M , Ardelean, C . CD117/c‐kit positive interstitial (Cajal‐like) cells in human pancreas. J Cell Mol Med. 2005; 9: 738–9. [Google Scholar]
- 10. Ciontea, SM , Radu, E , Regalia, T , Ceafalan, L , Cretoiu, D , Gherghiceanu, M , Braga, RI , Malincenco, M , Zagrean, L , Hinescu, ME , Popescu, LM . C‐kit immunopositive interstitial cells (Cajal‐type) in human myometrium. J Cell Mol Med. 2005; 9: 407–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Popescu, LM , Ciontea, SM , Cretoiu, D , Hinescu, ME , Radu, E , Ionescu, N , Ceausu, M , Gherghiceanu, M , Braga, RI , Vasilescu, F , Zagrean, L , Ardeleanu, C . Novel type of interstitial cell (Cajal‐like) in human fallopian tube. J Cell Mol Med. 2005; 9: 479–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hinescu, ME , Popescu, LM . Interstitial Cajal‐like cells (ICLC) in human atrial myocardium. J Cell Mol Med. 2005; 9: 972–975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Parrinello, S , Coppe, JP , Krtolica, A , Campisi, J . Stromalepithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci. 2005; 118: 485–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kveiborg, M , Frohlich, C , Albrechtsen, R , Tischler, V , Dietrich, N , Holck, P , Kronqvist, P , Rank, F , Mercurio, AM , Wewer, UM . A role for ADAM12 in breast tumor progression and stromal cell apoptosis. Cancer Res. 2005 Jun 1;65(11):4754–61. [DOI] [PubMed] [Google Scholar]
- 15. Allinen, M , Beroukhim, R , Cai, L , Brennan, C , Lahti‐Domenici, J , Huang, H , Porter, D , Hu, M , Chin, L , Richardson, A , Schnitt, S , Sellers, WR , Polyak, K . Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004; 6: 17–32. [DOI] [PubMed] [Google Scholar]
- 16. Adriance, MC , Inman, JL , Petersen, OW , Bissell, MJ . Myoepithelial cells: good fences make good neighbors. Breast Cancer Res. 2005; 7: 190–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Galie, M , Sorrentino, C , Montani, M , Micossi, L , Di Carlo, E , D'Antuono, T , Calderan, L , Marzola, P , Benati, D , Merigo, F , Orlando, F , Smorlesi, A , Marchini, C , Amici, A , Sbarbati, A . Mammary carcinoma provides highly tumourigenic and invasive reactive stromal cells. Carcinogenesis. 2005; 26: 1868–78. [DOI] [PubMed] [Google Scholar]
- 18. Popescu, LM , Andrei, F , Hinescu, ME . Snapshots of mammary gland interstitial cells: methylene‐blue vital staining and c‐kit immunopositivity. J Cell Mol Med. 2005; 9: 476–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Radu, E , Regalia, T , Ceafalan, L , Andrei, F , Cretoiu, D , Popescu, LM . Cajal‐type cells from human mammary gland stroma: phenotype characteristics in cell culture. J Cell Mol Med. 2005; 9: 748–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Popescu, LM , Gherghiceanu, M , Cretoiu, D , Radu, E . The connective connection: interstitial cells of Cajal (ICC) and ICC‐like cells establish synapses with immunoreactive cells. Electron microscope study in situ. J Cell Mol Med. 2005; 9: 714–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Pitelka, DR , Hamamoto, ST , Duafala, JG , Nemanic, MK . Cell contacts in the mouse mammary gland. I. Normal gland in postnatal development and the secretory cycle. J Cell Biol. 1973; 56: 797–818. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Moore, ED , Voigt, T , Kobayashi, YM , Isenberg, G , Fay, FS , Gallitelli, MF , Franzini‐Armstrong, C . Organization of Ca2+ release units in excitable smooth muscle of the guineapig urinary bladder. Biophys J. 2004; 87: 1836–47. Erratum in: Biophys J. 2004; 87:2914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Hennighausen, L , Robinson, GW . Information networks in the mammary gland. Nat Rev Mol Cell Biol. 2005; 6: 715–25. [DOI] [PubMed] [Google Scholar]
- 24. Guinebretiere, JM , Menet, E , Tardivon, A , Cherel, P , van El, D . Normal and pathological breast, the histological basis. Eur J Radiol. 2005; 54: 6–14. [DOI] [PubMed] [Google Scholar]
- 25. Fridriksdottir, AJ , Villadsen, R , Gudjonsson, T , Petersen, OW . Maintenance of cell type diversification in the human breast. J Mammary Gland Biol Neoplasia. 2005; 10: 61–74. [DOI] [PubMed] [Google Scholar]
- 26. Ozzello, L . Epithelial‐stromal junction of normal and dysplastic mammary glands. Cancer. 1970; 25: 586–600. [DOI] [PubMed] [Google Scholar]
- 27. Eyden, BP , Watson, RJ , Harris, M , Howell, A . Intralobular stromal fibroblasts in the resting human mammary gland: ultrastructural properties and intercellular relationships. J Submicrosc Cytol. 1986; 18: 397–408. [PubMed] [Google Scholar]
- 28. Eyden, B . The myofibroblasts: a study of normal, reactive and neoplastic tissue, with an emphasis on ultrastructure. Part 1 ‐ Normal and reactive cells. J Submicrosc Cytol Pathol. 2005; 37: 109–204. [PubMed] [Google Scholar]
- 29. Eyden, B . The myofibroblast: an assessment of controversial issues and a definition useful in diagnosis and research. Ultrastruct Pathol. 2001; 25: 39–50. [DOI] [PubMed] [Google Scholar]
- 30. Eyden, B . Fibroblast phenotype plasticity: relevance for understanding heterogeneity in “fibroblastic” tumors. Ultrastruct Pathol. 2004; 28: 307–19. [DOI] [PubMed] [Google Scholar]
- 31. Dvorak, AM . Mast cell secretory granules and lipid bodies contain the necessary machinery important for the in situ synthesis of proteins. Chem Immunol Allergy 2005; 85: 252–315. [DOI] [PubMed] [Google Scholar]
- 32. Galli, SJ , Kalesnikoff, J , Grimbaldeston, MA , Piliponsky, AM , Williams, CM , Tsai, M . Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005; 23: 749–86. [DOI] [PubMed] [Google Scholar]
- 33. Tukhtaev, KR , Khasanov, BB , Azizova, FKh . Structural and functional interrelations of immunocompetent cells in the mammary gland of lactating rats and in the small intestine of newborn rats during suckling period. Morfologiia 2003; 124: 70–2. [PubMed] [Google Scholar]
- 34. Zufarov, KA , Tukhtaev, KR , Khasanov, BB . Quantitative and ultrastructural characteristics of immunocompetent cells in the mammary gland during pregnancy and lactation. Morfologiia. 2003; 124: 74–9. [PubMed] [Google Scholar]
- 35. Cukierman, E . A visual‐quantitative analysis of fibroblastic stromagenesis in breast cancer progression. J Mammary Gland Biol Neoplasia. 2004; 9: 311–24. [DOI] [PubMed] [Google Scholar]
- 36. Maffini, MV , Calabro, JM , Soto, AM , Sonnenschein, C . Stromal regulation of neoplastic development: age‐dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol. 2005; 16: 1405–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Parmar, H , Cunha, GR . Epithelial‐stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer. 2004; 11: 437–58. [DOI] [PubMed] [Google Scholar]
- 38. Cunha, GR , Cooke, PS , Kurita, T . Role of stromal‐epithelial interactions in hormonal responses. Arch Histol Cytol. 2004; 67: 417–34. [DOI] [PubMed] [Google Scholar]
- 39. Rosen, PP . Rosen's breast pathology. 2nd ed. Philadelphia : Lippincott Williams & Wilkins; 2001. [Google Scholar]
