In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2016

In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium

Résumé

Scattered inflammatory cells are commonly observed in mammary gland tissue, most likely in response to normal cell turnover by proliferation and apoptosis, or as part of immunosurveillance. In contrast, lymphocytic lobulitis (LLO) is a recurrent inflammation pattern, characterized by lymphoid cells infiltrating lobular structures, that has been associated with increased familial breast cancer risk and immune responses to clinically manifest cancer. The mechanisms and pathogenic implications related to the inflammatory microenvironment in breast tissue are still poorly understood. Currently, the definition of inflammation is mainly descriptive, not allowing a clear distinction of LLO from physiological immunological responses and its role in oncogenesis remains unclear. To gain insights into the prognostic potential of inflammation, we developed an agent-based model of immune and epithelial cell interactions in breast lobular epithelium. Physiological parameters were calibrated from breast tissue samples of women who underwent reduction mammoplasty due to orthopedic or cosmetic reasons. The model allowed to investigate the impact of menstrual cycle length and hormone status on inflammatory responses to cell turnover in the breast tissue. Our findings suggested that the immunological context, defined by the immune cell density, functional orientation and spatial distribution, contains prognostic information previously not captured by conventional diagnostic approaches. Several studies provided conclusive evidence that a delicate balance between mammary epithelial cell proliferation and apoptosis regulates homeostasis in the healthy breast tissue 1-7. After menarche, and in the absence of pregnancy, the adult female mammary gland is subjected to cyclic fluctuations depending on hormonal stimulation 1,8. In response to such systemic hormonal changes, the breast epithelium undergoes a tightly regulated sequence of cell proliferation and apoptosis during each ovarian/menstrual cycle 1-3. The peak of epithelial cell proliferation has been reported to occur during the luteal phase, suggesting a synergistic influence of steroid hormones, such as estrogen and progesterone 2-5. In turn, the peak of apoptotic activity would be expected in response to decreasing hormone levels towards the end of the menstrual cycle 2-5. However, recent histologic findings indicate that apoptosis reaches its maximum levels in the middle of the luteal phase, although there is also a peak at about the third day of the menstrual cycle 6,7. Experimental measurements of cell turnover, i.e. programmed cell death and proliferation, demonstrated that an imbalance between the mitotic and apoptotic activity might lead to malignant transformation of epithelial cells and tumorigenic processes 9-11. Indeed, excessive cell proliferation promotes accumulation of DNA damage due to insufficient timely repair and mutations 12,13. There is also recent evidence that hormones suppress effective DNA repair and alter DNA damage response (DDR) 13-15 .
Fichier principal
Vignette du fichier
srep2016.pdf (4.45 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

hal-01878620 , version 1 (21-09-2018)

Identifiants

Citer

Juan Carlos López Alfonso, Nadine S Schaadt, Ralf Schönmeyer, Nicolas Brieu, Germain Forestier, et al.. In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium. Scientific Reports, 2016, 6 (1), ⟨10.1038/srep33322⟩. ⟨hal-01878620⟩

Collections

SITE-ALSACE IRIMAS
112 Consultations
21 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More