Lactoferrin is an iron – binding glycoprotein from the transferrin family which is predominantly found in the product of exocrine glands. It is first reported in 1939 by Sorensen et al. They discovered an occurrence of iron – containing protein in bovine milk. This protein is further studied in 1960, and characterized as similar to human serum transferrin. In fact, its affinity to iron is 300 times more than transferrin. The etymology of Lactoferrin has roots in the history of its discovery; ‘lacto-‘means milk in Latin, while ‘ferrin’ means iron binding.
As a matter of fact, despite its name, Lactoferrin is not exclusively found in breast milk. It is the product of exocrine glands which can be found in various part of human body, such as the digestive and respiratory system among others. Systemically, it is also secreted by the polymorphonuclear cells. Its role, likewise, is not constraint to merely iron binding and iron homeostasis. Studies had expressed its role in immunity, defense against infection and inflammation, regulation of cellular growth and differentiation and protection against cancer development and metastasis. These findings have suggested the role of Lactoferrin as great potential for cancer therapy; its prevention and treatment.
Carcinogenesis is a multistage mutation process which may take years before a cell turns cancerous. The process is not straightforward, human body is not defenseless against carcinogenesis; it is well equipped to detect and kill mutated cells. The mechanism involves expression of tumor suppressing gene, activation of natural killer cells among other mechanisms. Understanding the nature of carcinogenesis gives us insight that there are sufficient opportunities to intervene in this process, preventing or even reversing the process of carcinogenesis. Over the years, clinical studies had persistently support the positive correlation between nutrition and health. To fight carcinogenesis, our body needs resources which can be synthesized inherently or ingested from food. The body obtains its source of energy, micronutrients from the food it ingested. Hence, it is logical and empirical to incorporate into our diet, anti cancer agents, supporting and firing up the body natural defense mechanism against carcinogenesis. This chemopreventive agent must be inexpensive, widely available to benefit the general population.
A promising research is in Lactoferrin, a cancer preventive protein. This protein has been reported in vivo and in vitro to show anti – carcinogenesis properties (Baveye et al., 1999; Brock, 2002; Nuijens et al., 1996; Tsuda et al., 2000, 2002; Ward et al., 2002; Ushida et al., 1999; Sekine et al., 1997a; Iigo et al., 1999; Wang et al., 2000; Matsuda et al., 2006; Pan et al., 2007).
Lactoferrin is a single chain iron – binding protein. It is predominantly found excreted by exocrine gland located in the digestive, respiratory and reproductive systems. Lonnerdal in 2003 reported the occurrence of Lactoferrin secreted in breast milk, tears, synovial fluids, saliva and seminal fluid. Internally, it can be found in blood and plasma, mainly secreted by the neutrophils. Lactoferrin is synthesized by neutrophils during inflammation. Its protein structure closely resembles transferrin, the naturally occurring iron transporter in the human body. Nevertheless, Lactoferrin differs from transferrin in terms of its higher affinity for Iron, and exerting anti inflammation and anti – cancer activity. A study by Baker in 2002 supported that Lactoferrin has a more potent iron withholding ability.
Lactoferrin natural expression in the human body is both constitutive and inducible. Pentecost and Teng in 1986 showed that Lactoferrin is constitutively expressed in wet mucosa, namely the digestive tract and respiratory tract. Meanwhile its expression can also be induced, for example in the uterine tissue. Lactoferrin expression is estrogen inducible. In 1997, Close et al suggested that Lactoferrin expression in mammary epithelial cells is mediated by changes in the cell shape or its cytoskeletal actin configuration. This observation may explain the suppression of Lactoferrin expression in malignancy case, where the cell has lost its normal cytoskeletal configuration. Hence, suggesting the possibility of the need for external supplementation of Lactoferrin in case of malignancy.
Lactoferrin is synthesized by neutrophils, and is stored within neutrophils granules. The Lactoferrin containing granules can either be excreted into the blood when stimulated or be incorporated into the phagosomes (Maher et al., 1993, Van Snick et al., 1974). The secretion of Lactoferrin into the blood system demonstrated to be induced by various conditions such as increase in blood iron level, inflammation, infection, and during carcinogenesis. The pathway or regulation of its secretion is multifactorial, and will be better understood along with future researches. Studies had gathered enough evidences to explain the removal of Lactoferrin from the human body. Olofsson et al., in 1977 suggested its removal involving endocytosis by the RES (reticuloendothelial system) cells such as the macrophages and monocytes. Bennet and Kokocinski in 1979 proved that labeled Lactoferrin is removed by the liver and spleen. Hutchens et al., in 1991 proved that Lactoferrin is also cleared by the kidney and excreted in the urine.
Lactoferrin antibacterial activity is reported by Santagati et al., in 2005, Valenti et al., in 1998 and Levay et al., in 1995. The main mechanism is by inhibiting growth of bacteria by reducing iron level required by bacteria to multiply, binding to LPS (lipopolysaccharide) tagging the bacteria aiding its clearance by the phagocytes.
Lactoferrin also shows immunomodulating activity. Lactoferrin was shown by Dhennin et al., in 2000 to stimulate production and raise activity of T and B lymphocytes and NK (Natural Killer cells), which then release various cytokines and thus increase the phagocytotic and cytotoxic activity of RES cells. Adamik et al., in 1998 and Bennet et al., in 1981 also reported Lactoferrin accelerating the maturation of the lymphocytes, B and T cells and elevate the expression of several types of cellular receptors.
Iron is a necessary element for cellular function especially cellular proliferation. The significance of iron for human body is reflected in our body elaborate mechanism to uptake, transport, regulate and store iron to ensure that the body iron need will be met. Any excess iron will be stored intracellularly bound to ferritin. The storage mechanism is crucial to keep free iron in the blood low. While iron is essential for the cell, high level of blood iron is paradoxically damaging to the body. Free iron in the blood generated free radicals which may damage the cells, phenomena balanced by the cellular defense and DNA repair mechanisms. While iron supplementation is widely accepted today, there have been concerns about potential damaging effects. Weinberg in 1984, 1992; Selby and Friedman in 1988; Stevens et al., in 1988, proved that iron enhances colon and mammary carcinogenesis in rodents, and increase the risk of several cancers in humans. Some evidences also support the involvement of iron metabolism in breast cancer. Weinstein et al., in 1982 measured a six fold increase in tissue ferritin concentration in breast cancer compared to normal tissue. Transferrin receptor proteins are also elevated in breast cancer as compared to normal cells. All these evidences together indicate that iron enhances carcinogenesis in humans. Since proliferating cancer cells require iron, continuous supplementation of cancer cells with iron through upregulation of transferrin receptor will certainly enhance its proliferation rate.
Lactoferrin anti – cancer activity can be attributed to its iron – binding property. Free radical is a known cancer causing agent. It inflicts damage to nuclear level, causing disruption in nucleic acid structure, a process known as mutation. Since iron is a known free radical generator, by scavenging free plasma iron, keeping it low, Lactoferrin helps prevent the mutagenic consequences of free circulating iron. Apart from preventative property, Lactoferrin also exerts anti proliferative activity, by means of limiting the availability of iron to cancer cells, thus limiting their proliferation. This is observed especially in estrogen – dependent neoplasm such as breast and uterine cancers in studies done by Weinstein et al., in 1982 and Elliot et al., in 1993. The latter development can be prevented by iron chelators.
Apart from iron – binding activity, Lactoferrin also exert other anti – cancer mechanisms. In a study by Damien et al., in 1998, and Matsuda et al., in 2006, Lactoferrin administration proved to significantly modulate NK cell cytotoxicity. The studies involved pre – treating NK cells or target cells with Lactoferrin, and the results reflected Lactoferrin modulates NK cell cytotoxicity and target cell sensitivity to lysis. Studies also exhibited that Lactoferrin inhibits epithelial cells proliferation by intervening in cell cycle progression. They proved that Lactoferrin induced cellular growth arrest at the G1 to S phase. This was carried about by modulation of the expression and activity of specific regulatory proteins.
Studies in rat which involves the oral administration non iron – bound Lactoferrin, showed result that Lactoferrin significantly inhibit VEGF165 – mediated angiogenesis response. Thus, giving rise to potential use of Lactoferrin as anti –angiogenesis treatment.
In another study by Yoo et al., in 1997, LFCin, a derivative of Lactoferrin was shown to induce apoptosis in THP – 1 human monocytic leukemic cells. The activity was believed to be mediated by the modulation of intracellular reactive oxygen species (ROS) and activation of Ca2+/Mg2+ dependent endonucleosis.
In a recent clinical study by Tarek M. Moastada et al., in 2014 on the therapeutic benefit of Lactoferrin in patients with colorectal cancer receiving chemotherapy, a double – blinded parallel randomized controlled trial was conducted. The result suggested that oral bovine Lactoferrin administration has significant therapeutic effect on colorectal cancer patients. The study also suggested that daily administration of Lactoferrin showed clinically beneficial effect on patients with colorectal cancer.
Finally, Lactoferrin a naturally occurring iron binding protein with multitudes of benefit, and anti cancer activity, continuously be proven to be a potent anti – cancer agent. Its natural occurrence in the human body system renders it safe, and administration of this agent will support the body to fight carcinogenesis.