Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Abstract

Purpose: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma. Experimental Design: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth. Results: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G 1 -G 0 growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-a. Lactoferrin up-regulated the cellular activation of nuclear factor-nB within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3 + cells, all lactoferrin-induced tumor inhibition was abrogated. Conclusion: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.

Lactotransferrin: A candidate tumor suppressor—Deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen‐activated protein kinase pathway

“…Our data are consistent with recent observations in head and neck squamous cell carcinoma in vivo. 38 Inhibition of NPC cell growth by LTF treatment is likely mediated by NPC-induced cell cycle arrest. Notably, 1 NPC cell line, 6-10B, was resistant to LTF-mediated growth inhibition and cell cycle arrest in our experimental system, even though all cell lines tested had lost LTF expression.…”

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

“…Therefore, increased recruitment of neutrophils and compliment with an increase of lactoferrin production by epithelial cells occurs in the initial phase of infection. Although there has been extensive research efforts on the structure-function relationship of LF and its application in nutritional supplement and prevention of infections and cancers [8][9][10][11][12], studies on the regulation of LF expression by physiological stimuli has been limited [13,14].…”

The Antiproliferative Effect of Bovine Lactoferrin on Canine Mammary Gland Tumor Cells

“…Recently, some studies have also suggested antitumor activities for LF [2,6,9,13,14]. In previous studies, LF has been shown to inhibit the growth of some tumor cell lines, including head and neck squamous cell carcinoma (SCCVII, O12), human breast cancer epithelial cells (MCF-7, MDA-MB-231) and murine colon adenocarcinoma cells (colon-26) [2,6,9,13,14].…”

“…In previous studies, LF has been shown to inhibit the growth of some tumor cell lines, including head and neck squamous cell carcinoma (SCCVII, O12), human breast cancer epithelial cells (MCF-7, MDA-MB-231) and murine colon adenocarcinoma cells (colon-26) [2,6,9,13,14]. Furthermore, phase I trials of talactoferrin alfa, a recombinant human lactoferrin, have been completed using human refractory solid tumors [4].…”

“…This cell cycle control system breaks down in tumor cells. Lactoferrin has been shown to inhibit G1 cyclin-dependent kinases in human breast carcinoma cells [2], downregulate G1 cyclin-dependent kinases in head and neck cancer cells [13] and control the level and activity of retinoblastoma protein (pRB) [11]. These reports also raise interesting questions about the effects of LF on the canine tumor cell cycle.…”