Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Abstract

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine Interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients, and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER− primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET–derived full length IL-8(1–77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6–77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7 days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28 days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

The Role of Interleukin-8 and Its Mechanism in Patients with Breast Cancer: Its Relation with Oxidative Stress and Estrogen Receptor

“…Another study confirmed previous study and reported that IL-8 is associated with stage disease, detected as a prognostic factor (13,14). Kamalakar reported that interleukin-8 plays a main role in osteolysis of patients with breast cancer, and anti-interleukin-8 therapy may be useful in the treatment of skeletal-related events associated with breast cancer (15). However, Zuccari et al reported that the decreased level of IL-8 is associated with local recurrence and/or metastasis in patients with breast cancer (4).…”

“…Furthermore, the existence of ER-α and ER-β in ER negative cancer cells decreased the expression of IL-8 about 40% (23). Kamalkar et al showed that primary human invasive ductal carcinoma may have IL-8 and its expression dose not correlate to Estrogen receptor status (15). Besides, Estrogen activity inhibition with anti-estrogens did not increase the expression of interleukn-8 in breast cancer cells (23).…”

Chemical and physical properties of carbonated hydroxyapatite affect breast cancer cell behavior

“…IL-8 is of particular interest as elevated levels of this chemotactic and inflammatory chemokine have been linked to various aspects of malignancy including increased tumor angiogenesis, invasion, and bone-metastatic capability of breast cancer [21, 22]. For example, the more invasive character of estrogen (ER) negative vs. ER positive breast cancer cells is related to increased levels of IL-8 [23].…”

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

“…IL-8, a prototypical member of a superfamily of small, inducible, secreted CXCs (chemokines) or α-chemokines originally identified as monocyte-derived factors capable of attracting and activating neutrophils, is expressed by a number of cancer cell lines in vitro. Numerous correlations were observed between breast cancer tumor cell IL-8 expression, plasma levels of IL-8, and metastatic potential to bone [54,68,69], also evaluating how chemical and physical properties of specific biomineralized culture platforms can alter breast cancer cell growth and secretion of tumorigenic IL-8 [70]. Increased levels of IL-8 were also highlighted in sera of mice with bone metastases and, together with IL-6, it might be responsible for the attraction of cancer stem-like cells to bone and might support the phenotypic switch [53].…”