Premium
Positive lymph‐node breast cancer patients – activation of NF ‐κB in tumor‐associated leukocytes stimulates cytokine secretion that promotes metastasis via C‐C chemokine receptor CCR 7
Author(s) -
ElGhonaimy Eslam A.,
ElShinawi Mohamed,
Ibrahim Sherif A.,
ElGhazaly Hisham,
AbdElTawab Reda,
Nouh Mohamed A.,
ElMamlouk Tahani,
Mohamed Mona M.
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13124
Subject(s) - cytokine , metastasis , breast cancer , cancer research , chemokine , tumor microenvironment , medicine , tumor necrosis factor alpha , chemokine receptor , immunology , receptor , cancer
Tumor metastasis to lymph nodes is most deadly complication among breast cancer patients. Herein, we investigated the molecular mechanism by which tumor‐associated leukocytes ( TAL s) mediate lymph node metastasis. The density of different leukocyte subtypes infiltrating the tumor microenvironment of negative and positive lymph nodes ( nLN s, pLN s) in breast cancer patients was measured using immunohistochemistry. In addition, we isolated TALs from blood drained from the axillary tributaries of nLN and pLN patients during breast surgery. Secretions of TAL s were subjected to cytokine profiling using a cytokine antibody array. Our results showed an increase in the number of infiltrated CD 45+ cells in the carcinoma tissues of pLN patients with the major proportion being myeloid subsets compared with nLN patients. Furthermore, TAL s of pLN patients show a significant fivefold increase in the secretion of interleukin ( IL )‐1α, interferon‐γ, IL ‐5, IL ‐3 and tumor necrosis factor‐β, and are characterized by enhanced constitutive NF‐κB/p65 signaling compared with TAL s isolated from nLN patients. Using an invasion assay, cytokines secreted by TAL s of pLN patients were shown to augment the invasive phenotype of breast cancer MCF ‐7 and SKBR 3 cells compared with nLN patients. Using flow cytometry, we found that C‐C chemokine receptor 7 (CCR7) is significantly overexpressed in breast carcinoma of pLN patients compared with nLN s patients. Intriguingly, CCR 7, a mechanistic clue for metastasis, is upregulated in MCF ‐7 cells upon stimulation with TAL ‐conditioned media of pLN patients. Our findings show that the molecular cues secreted by TAL s alone or in combination with CCR 7 may emerge as future therapeutic targets for lymph node metastasis in breast cancer patients.