lactoferrin and Adenocarcinoma

Localised seminal vesicle amyloidosis is relatively infrequent and we present 9 additional cases.. and methods: Those 9 cases were retrospectively retrieved from 803 radical prostatectomies performed between 1995 and 2000 for prostatic adenocarcinoma. In each case, the type of amyloidosis was characterised by immunohistochemistry. Information regarding a possible concurrent disease or prior hormone therapy has been obtained.. The prevalence of amyloidosis of seminal vesicles is lower in our study (1.1%) than in unselected autopsy cases. The prevalence of amyloidosis in patients exposed to prior hormone therapy (LHRH agonist and anti-androgen) was 2% while it reached only 0.9% in those who received no hormone therapy (p>0.3). No patient had systemic amyloidosis and all cases were of non A-A type. Lactoferrin, a glycoprotein produced by normal seminal vesicles, was detected in more than a half of them (5/9).. No association was found between the occurrence of seminal vesicle amyloidosis and occurrence of a prostatic adenocarcinoma, corcomitant systemic disease or exposure to prior hormone therapy. Seminal vesicle amyloidosis is a localised condition without systemic involvement and amyloid deposition is composed mostly of lactoferrin.

Topics: Adenocarcinoma; Adult; Aged; Amyloid; Amyloidosis; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; France; Genital Diseases, Male; Gonadotropin-Releasing Hormone; Humans; Lactoferrin; Male; Middle Aged; Neoadjuvant Therapy; Prevalence; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Seminal Vesicles

Lactoferrin (LTF) is an iron-binding protein canonically known for its innate and adaptive immune functions. LTF may also act as a tumor suppressor with antiproliferative action. LTF is inactivated genetically or epigenetically in various cancers, and a CpG island spanning the transcriptional start site of LTF is hypermethylated in prostate cancer cell lines. We, therefore, hypothesized that LTF expression is silenced via CpG island hypermethylation in the early stages of prostate tumorigenesis carcinogenesis. Targeted methylation analysis was performed using a combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes, and laser-capture microdissection followed by bisulfite sequencing on DNA isolated from prostate tissue samples, including both primary and metastatic disease. LTF mRNA in situ hybridization and LTF protein immunohistochemistry were also performed. We report that the LTF CpG island is frequently and densely methylated in high-grade prostatic intraepithelial neoplasia, primary prostate carcinoma, and metastases. We further report a decoupling of lactoferrin mRNA and protein expression, including in lesions where LTF mRNA has presumably been silenced via CpG island methylation. We conclude that LTF mRNA expression is silenced in prostate tumorigenesis via hypermethylation, supporting a role for LTF as a prostate cancer tumor suppressor gene. Likewise, the frequency at which the LTF CpG island is methylated across samples suggests it is an important and conserved step in prostate cancer initiation.

Topics: Adenocarcinoma; Carcinogenesis; Cell Line, Tumor; CpG Islands; Disease Progression; DNA Methylation; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Lactoferrin; Male; Neoplasm Staging; Promoter Regions, Genetic; Prostatic Neoplasms; RNA, Messenger

Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28 µm and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.

Topics: A549 Cells; Adenocarcinoma; Administration, Inhalation; Animals; Antineoplastic Combined Chemotherapy Protocols; Berberine; Chemistry, Pharmaceutical; Drug Carriers; Drug Delivery Systems; Humans; Hyaluronic Acid; Hydrophobic and Hydrophilic Interactions; Lactoferrin; Lung Neoplasms; Male; Mice; Nanocomposites; Phospholipids; Sirolimus

Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation.. Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats.. 5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin.. Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Carriers; Fluorouracil; Humans; Lactoferrin; Nanoparticles; Oxaliplatin; Rats, Wistar; Tissue Distribution

Efficient early detection of cancer and its simultaneous therapy can improve the survival of cancer patients significantly. Recently there is great interest for the development of nanotheranostic systems with multimodal live real-time imaging ability. Novel multimodal multifunctional iron oxide (Fe3O4) saturated lactoferrin (FebLf) nanocapsules/nanocarriers (FebLf NCs) nanoformulation was fabricated. Anti-cancer nanotheranostic ability in human xenograft colonic adenocarcinoma model was conducted in vivo by employing near infrared flouroscence (NIRF) real time live mice imaging technology. FebLf NCs showed spherical morphology with 50 to 80 nm size with super paramagnetic property and exhibited profound in vivo anti-tumour efficacy, leading to regression of the xenograft colonic tumour growth over a 90 day trial period. NIRF real time imaging revealed selective localisation patterns of the FebLf NCs at the tumour site causing tumour growth inhibition. In turn, ex vivo NIRF imaging of mice organs showed enhanced tumoural uptake and biodistribution at the vital organs including spleen, intestine, kidney, and intestine. Low-density lipoprotein receptors (LDLRs), ferroportin, ferritin receptor based in vivo internalisation mechanisms and iron metabolism regulation were observed. Histopathological analysis revealed obsolute non-toxic nature of FebLf NCs in mice tissues. These observations summate biocompatible, multimodal anticancer activity of novel FebLf NCs for real time cancer therapeutic imaging leading to targeted colonic adenocarcinoma therapy.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Colonic Neoplasms; Humans; Lactoferrin; Magnetite Nanoparticles; Mice; Nanocapsules; Spectroscopy, Near-Infrared; Theranostic Nanomedicine; Tissue Distribution; Xenograft Model Antitumor Assays

The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1(+)/CIMP2(-)/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER(-)/PR(-)/HER2(-); MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm(3), and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm(3). In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm(3) within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy.

Topics: Adenocarcinoma; Animals; Carrier Proteins; Cattle; Colonic Neoplasms; Female; Ferric Compounds; Humans; Lactoferrin; Mice; Mice, Nude; Nanocapsules; Theranostic Nanomedicine; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinc

Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p < 0.001) in reducing LC50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance.

Topics: Adenocarcinoma; Animals; Apoptosis; Cattle; Cell Line, Tumor; Chemokine CCL17; Chemokine CCL4; Doxorubicin; Drug Carriers; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Interferon-gamma; Iron; Lactoferrin; Male; Mice; Mice, Transgenic; Neoplasm Proteins; Prostatic Neoplasms; Spheroids, Cellular; Topoisomerase II Inhibitors; Tumor Necrosis Factor-alpha

This is the first report describing the expression of canine calreticulin (cCRT) in canine mammary gland tumour (MGT). Using cDNA subtraction method, it is found that mRNAs of CRT, cathepsin A, ovostatin, and lactotransferrin were differentially expressed in mammary adenocarcinoma as compared to hyperplasia, both of which were obtained from the dog. Furthermore, the mRNA expression levels of CRT and cathepsin A were significantly higher in canine MGT samples than in nontumour samples. In contrast, immunohistochemical studies have indicated that the expression of cCRT protein found to be detected in most of mammary gland tissues and was not correlated to the types of canine MGTs. Furthermore, cCRT was molecularly cloned, and the amino acid sequence of cCRT was found to be very similar to those of other species. Further studies are required to elucidate additional roles of cCRT in canine MGT.

Topics: Adenocarcinoma; alpha-Macroglobulins; Animals; Base Sequence; Biomarkers, Tumor; Blotting, Western; Calreticulin; Cathepsin A; Cell Line, Tumor; Dog Diseases; Dogs; Female; Gene Library; Lactoferrin; Mammary Neoplasms, Animal; Molecular Sequence Data; Real-Time Polymerase Chain Reaction; RNA, Messenger

Lactoferrin (Lf), an iron-binding protein present in mammalian secretions, plays important roles in cancer prevention by inducing apoptosis.. PC-14 lung adenocarcinoma cells were exposed to bovine Lf (bLf) protein and the expression of caspase-3 and apoptosis protease-activating factor-1 (APAF-1) was assessed. To investigate the molecular mechanism of apoptosis induced by bLf, a major Lf-binding protein was screened using a protein microarray with bLf protein as the probe. Protein interaction was demonstrated by co-immunoprecipitation, immunofluorescence and phosphatase activity assay.. Lf directly suppressed the proliferation of the PC-14 cells by triggering their apoptosis. Lf was shown to bind specifically with a 36-kDa protein, immunoglobulin (CD79A)-binding protein 1 (IGBP1). The binding complex interacted with the catalytic subunit of protein phosphatase 2A (PP2A), thus reducing the phosphatase activity of PP2A and triggering apoptosis.. Lf binds IGBP1 and promotes the acceleration of cellular apoptosis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Apoptosis; Cattle; Cell Growth Processes; Cell Line, Tumor; Humans; Intracellular Signaling Peptides and Proteins; Lactoferrin; Lung Neoplasms; Microscopy, Fluorescence; Molecular Chaperones; Protein Array Analysis; Reverse Transcriptase Polymerase Chain Reaction

Chromosomal DNA sequence polymorphisms may contribute to individuality, confer risk for diseases, and most commonly are used as genetic markers in association study. The iron-binding protein lactoferrin inhibits bacterial growth by sequestering essential iron and also exhibits antitumor, anti-inflammatory, and immunoregulatory activities. The gene coding for lactotransferrin (LTF) is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can affect LTF functions. In this study, we determined the distribution of LTF gene polymorphisms (rs1126477, rs1126478, rs2073495, and rs9110) in the Chinese Han population and investigated whether these polymorphisms were associated with increased risk of ovarian carcinoma in the Chinese. It was found that the rs1126477 was correlated significantly with ovarian cancer. The frequency of A allele of rs1126477 was significantly higher in 700 ovarian cancer patients compared with that in the control group of 700 cases (P< 0.01, χ(2)= 6.79). The frequency of AA genotype was significantly higher in ovarian cancer patients compared with that in the control group (P< 0.05, χ(2)= 6.49). AA genotype is the risk factor of ovarian cancer. The odds ratio (OR) was 2.24 and the 95% confidence interval (CI) was 1.08-4.59, respectively. The 'A-G-C-C' haplotype constructed with rs1126477, rs1126478, rs2073495, and rs9110 was the risk factor to be ovarian cancer. The expression of LTF gene was lower in individuals with 'A-G-C-C' haplotype compared with that in individuals without 'A-G-C-C' haplotype. These findings suggested that rs1126477 could play important roles in ovarian carcinoma physiological processes in the Chinese.

Topics: Adenocarcinoma; Adult; Aged; Asian People; Case-Control Studies; Female; Gene Expression; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Lactoferrin; Middle Aged; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Risk Factors

Lactoferrin, a protein from bovine milk belonging to the transferring family proteins, contains 2 bound Fe(+3) ions. Recent research has revealed that lactoferrin exhibits not only antimicrobial activity by its high affinity for Fe(+3) but also remarkable anticancer capacity in cancer cell lines. Meanwhile, increasing evidence suggests that aberrant activation of Akt is involved in both normal cells and human cancers and that inhibition of Akt signaling pathway might be a promising strategy for cancer treatment. In the present study, we investigated the effect of the antitumor induced by exposing stomach cancer cell SGC-7901 to lactoferrin for 24 and 48 h. The cell viability was assessed by 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay and apoptosis was quantified by propidium iodide uptake and Annexin V-fluorescein isothiocyanate fluorescent probe label through flow cytometry. Our investigation indicates that inhibitory ratio of 50 microM lactoferrin for proliferation of stomach cancer cell SGC-7901 is much higher than 12.5 and 25 microM, and for the extended treatment time, the concentration of 50 microM has more efficiency than 100 microM lactoferrin. To elucidate a mechanism involved in its antitumor effect, we studied the Akt cell signaling pathway of SGC-7901 while treated by 50 microM of lactoferrin after 0, 24, and 48 h, particularly Akt phosphorylation of 2 individual residues, Ser473 and Thr308, Akt/glycogen synthase kinase-3beta, forkhead in human rhabdomyosarcoma, and nuclear factor-kappaB proteins, respectively, activated by Western blot. The expressions of Akt, phosphorylated Akt Ser473, phosphorylated Akt Thr308, phosphorylated nuclear factor-kappa b p65 Ser536, and Bcl-2 significantly decreased; however, the expressions of phosphorylated glycogen synthase kinase-3beta Ser9, phosphorylated forkhead in human rhabdomyosarcoma Ser256, and phosphorylated caspase-9 Ser196 increased in response to lactoferrin treatment in SGC-7901. These results suggest that lactoferrin inhibits Akt activation and modulates its downstream proteins phosphorylation in apoptosis of SGC-7901 human stomach cancer cells.

Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Cattle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lactoferrin; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms

Lung cancer is one of the most common cancers in the world, and the incidence of lung cancer is increasing. Risk analysis of environmental chemicals on lung carcinogenesis is particularly important. Detection of chemopreventive agents of lung carcinogenesis is also important to reduce our risk of lung cancer. For that purpose, it is necessary to establish reliable in vivo animal models of lung carcinogenesis. The A/J mouse is a mouse strain sensitive to lung carcinogens, and also develops spontaneous lung tumors without any chemical treatment. We have demonstrated that a treatment of 4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone (NNK), a tobacco specific nitrosamine, or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (MeIQx), a heterocyclic amine, induced lung tumors in the female A/J mouse in 16 and 32 weeks. The lung tumors developed in the A/J mouse are histopathologically classified as adenocarcinomas, adenomas, and alveolar cell hyperplasias. Some of these types of lung cancer are similar to those of human lung cancer. We also investigated the chemopreventive effects of bovine LF (bLF) on different phases of NNK-induced lung tumorigenesis in A/J mice. The A/J mouse is very useful mouse strain as a reliable in vivo model, which can be used for risk analysis of lung carcinogenesis.

Topics: Adenocarcinoma; Adenoma; Animals; Carcinogens; Cattle; Disease Models, Animal; Female; Humans; Lactoferrin; Lung Neoplasms; Male; Mice; Mice, Inbred A; Mice, Inbred ICR; Nitrosamines; Risk Assessment

Lactoferrin has several biological activities, including antitumor activities in some human and animal tumor cells. Clinical trials have been carried out in human medicine based on these effects. However, the antitumor effects of lactoferrin in veterinary medicine remain unknown. In this in vitro study, we demonstrated that co-incubation of canine mammary gland tumor cells (CIPp and CHMp) and bovine lactoferrin induced growth arrest of tumor cells. This growth arrest was associated with induction of G1 arrest. Furthermore, this effect was stronger in tumor cells than in normal cells. These findings demonstrate that bovine lactoferrin has anti-tumor activity in canine mammary tumors and has the potential for use in tumor-bearing dogs.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cattle; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Lactoferrin; Mammary Neoplasms, Animal; Time Factors

We have previously shown that talactoferrin-alfa (TLF), a recombinant human lactoferrin, is an immunomodulatory protein that is active against implanted tumors, both as a single agent and in combination with chemotherapy. In this study, we show that talactoferrin is active against autochthonous tumors in a transgenic mouse line, which is more analogous to human cancers, and identify key mechanistic steps involved in the anticancer activity of oral TLF. BALB/c mice transgenic for the rat neu (ErbB2) oncogene (BALB-neuT) treated with oral TLF showed a significant delay in carcinogenesis, with 60% tumor protection relative to vehicle-treated mice at week 21. Oral TLF also showed tumor growth inhibition in wild-type BALB/c mice implanted with neu(+) mammary adenocarcinoma, with one third displaying a long-lasting or complete response. Oral TLF induces an increase in intestinal mucosal IFN-gamma production and an increase in Peyer's patch cellularity, including expansion of CD8(+) T lymphocytes and NKT cells, and the enhancement of CD8(+) T-cell cytotoxicity. In IFN-gamma knockout mice, there is an absence of the TLF-induced Peyer's patch cellularity, no expansion of CD8(+) T lymphocytes and NKT cells, and loss of TLF anticancer activity. TLF antitumor activity is also lost in mice depleted of CD8(+) T cells and in CD1 knockout mice, which lack NKT activity. Thus, the inhibition of distant tumors by oral TLF seems to be mediated by an IFN-gamma-dependent enhancement of CD8(+) T- and NKT cell activity initiated within the intestinal mucosa.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Female; Interferon-gamma; Killer Cells, Natural; Lactoferrin; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Peyer's Patches; Receptor, ErbB-2

Lactoferrin and lysozyme are important antimicrobial compounds of airway surface liquid, derived predominantly from serous cells of submucosal glands but also from surface epithelium. Here we compared release of these compounds from the following human cell cultures: primary cultures of tracheal epithelium (HTE), Calu-3 cells (a lung adenocarcinoma cell line frequently used as a model of serous gland cells), 16HBE14o- cells (an SV40 transformed line from airway surface epithelium), T84 cells (a colon carcinoma cell line), and human foreskin fibroblasts (HFF). For lysozyme, baseline secretory rates were in the order Calu-3 > 16HBE14o- > HTE T84 > HFF = 0; for lactoferrin, the only cell type showing measurable release was HTE; for mucus, HTE > Calu-3 > 16HBE14o- T84 > HFF = 0. A wide variety of neurohumoral agents and inflammatory stimuli was without effect on lactoferrin and lysozyme release from HTE or Calu-3 cells, although forskolin did stimulate secretion of water and lysozyme from Calu-3 cells. However, the concentration of lysozyme in the forskolin-induced secretions was much less than in airway gland secretions. Thus our data cast doubt on the utility of Calu-3 cells as a model of airway serous gland cells but do suggest that HTE could prove highly suitable for studies of mucin synthesis and release.

Topics: Adenocarcinoma; Cell Line, Transformed; Cell Line, Tumor; Fibroblasts; Humans; Lactoferrin; Lung Neoplasms; Mucus; Muramidase; Respiratory Mucosa; Trachea

To study the histological and immunohistochemical characteristics of oncocytic carcinoma of salivary gland.. 7 cases of oncocytic carcinoma of salivary gland were investigated by HE, PAS, PTAH staining and immunohistochemistry.. Among the cases, 4 were male and 3 were female. The average age was 49 years old. 3 cases occurred in the parotid, 1 cases in submandibular, 1 cases in sublingual and 2 cases in minor salivary gland of palate. Investigated histologically, the tumour cells are characterized by oncocyte. The evidence of cellular atypia, obviously increased mitoses and infiltrative growth pattern are indicative of malignancy. Immunohistochemically, alpha 1-ACT, alpha 1-AT, LF, TF and CEA were all strongly positive in the normal salivary cells and adenolymphoma, while in oncocytic carcinoma, alpha 1-ACT and alpha 1-AT were moderate positive and LF, TF and CEA were light positive.. 7 cases were characterized by oncocyte and showing infiltrative growth, alpha 1-ACT, alpha 1-AT, LF, TF, CEA were positive in oncocyte.

Topics: Adenocarcinoma; Adult; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Carcinoembryonic Antigen; Female; Humans; Lactoferrin; Male; Middle Aged; Salivary Gland Neoplasms; Transferrin

Milk and dairy products constitute an important part of the western style diet. A large number of epidemiological studies have been conducted to determine effects of consumption on cancer development but the data are largely equivocal, presumably reflecting the different included components. It has been proposed that whereas fats in general could promote tumor development, individual milk fats like conjugated linoleic acid could exert inhibitory effects. There is also considerable evidence that calcium in milk products protects against colon cancer, while promoting in the prostate through suppression of circulating levels of 1,25-dihydroxyvitamin D3. Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity. The incidence of adenocarcinomas in the groups receiving 2% and 0.2% bLF were thus 15% and 25%, respectively, in contrast to the 57.5% control value (P<0.01 and P<0.05, respectively). Results in other animal models have provided further indications that bLF might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers.

Topics: Adenocarcinoma; Animals; Azoxymethane; Carcinogens; Colonic Neoplasms; Dairy Products; Diet; Dose-Response Relationship, Drug; Intestinal Polyps; Intestines; Lactoferrin; Male; Mice; Mice, Inbred C57BL; Milk; Rats; Rats, Inbred F344

The effects of lactoferrin (Lf), an iron-binding glycoprotein, on cell migration were investigated. Lf inhibited the cell migration of three gastrointestinal cell lines (Caco-2 cells, AGS cells, and IEC-18 cells) in vitro. Both iron-saturated (holo) and iron-depleted (apo) Lf showed this inhibitory effect. Chelation of iron in the culture medium by desferrioxamine did not affect the activity of either form of Lf. A pepsin hydrolysate of Lf exhibited effectiveness similar to that of intact Lf. These results demonstrate a novel activity of Lf and suggest a potential role for this molecule in gastrointestinal wound healing, which is independent of its iron-binding capacity.

Topics: Adenocarcinoma; Animals; Apoproteins; Cattle; Cell Movement; Colonic Neoplasms; Deferoxamine; Digestive System Physiological Phenomena; Humans; Intestinal Mucosa; Kinetics; Lactoferrin; Rats; Stomach Neoplasms

The influence of bovine lactoferrin (bLF) on colon carcinogenesis was investigated in male F344 rats treated with azoxymethane (AOM). Following three weekly injections of AOM, the animals received 2 or 0.2% bLF for 36 weeks. No effects indicative of toxicity were noted, but significant reduction in both the incidence and number of adenocarcinomas of the large intestine was observed with both doses. Thus, the incidences of adenocarcinomas in the groups receiving 2% and 0.2% bLF were 15% and 25%, respectively, in contrast to the 57.5% control value (P < 0.01 and P < 0.05, respectively). The results indicate that bLF might find application for chemoprevention of colon cancer.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Azoxymethane; Carcinoma; Cattle; Colonic Neoplasms; Incidence; Intestinal Neoplasms; Intestine, Large; Intestine, Small; Lactoferrin; Male; Rats; Rats, Inbred F344

The incidence of cervical adenocarcinomas in young women over the last two decades has increased. Even with increasing knowledge of the role of human papillomavirus in the etiology of adenocarcinoma of the cervix, there is a paucity of data concerning the genetic and epigenetic factors that contribute to the histologic features and biologic behaviors of these tumors. Lactoferrin is a basic glycoprotein found in human milk, secondary granules of neutrophils, and many body secretions, and it has been associated with carcinogenesis of the endometrium, breast, and lymphoid systems. In this study, we examined the expression of lactoferrin in normal human endocervical epithelium and in cervical adenocarcinomas in relation to proliferative index, steroid receptor status, p53 protein expression, and apoptosis. Immunohistochemical and in situ studies demonstrated that lactoferrin protein and mRNA were strikingly downregulated upon neoplastic transformation of the endocervix as early as in adenocarcinoma in situ when compared with the prominent expression exhibited by the normal cervical epithelium. Furthermore, neoplastic transformation of endocervical epithelial cells was accompanied by a pronounced stimulation of proliferation and a substantial reduction in the expression of the estrogen and progesterone receptors and p53 but little or no change in the number of apoptotic cells. In conclusion, we identified lactoferrin as a novel cancer-specific marker of endocervical adenocarcinomas that may be useful in the early detection of the disease, prediction of prognosis, and the development of new therapeutic modalities.

Topics: Adenocarcinoma; Cell Death; Cell Division; Cell Transformation, Neoplastic; Cervix Uteri; Down-Regulation; Female; Humans; Immunohistochemistry; In Situ Hybridization; Lactoferrin; Neoplasm Invasiveness; Phenotype; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; RNA, Neoplasm; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

In vitro studies of endometrial carcinogenesis have been hampered by dedifferentiation of the cells in culture. Using the endometrial carcinoma cell line HEC-1B(L), we aimed to establish and characterize culture conditions that preserve a more differentiated state of the tumor cells. HEC-1B(L) cells grown in a serum-free defined medium on plastic (PL/SFDM) on top of a reconstituted basement membrane (Matrigel, MG/SFDM) or in a thick layer of Matrigel showed pronounced morphological differentiation as compared with HEC-1B(L) cells cultured on plastic in a medium containing serum (PL/10% FCS). Features of differentiation included cuboidal to columnar cell shape and an increase of rough endoplastic reticulum in Matrigel cultures. Gene expression of HEC-1B(L) cells was studied by metabolic [35S]methionine labeling and SDS-gel electrophoresis. HEC-1B(L) cells cultured in the presence of Matrigel showed two additional secretory proteins approximately 31 kD and 77 kD in size. rt-PCR was used to screen cell cultures for the presence of estrogen receptor, progesterone receptor, and lactoferrin-mRNA, genes typically expressed by normal endometrial epithelium. We found no expression of the estrogen receptor or progesterone receptor. Lactoferrin-mRNA was present under all culture conditions tested. Our results suggest a regulatory role of the extracellular matrix for the differentiation of the HEC-1B(L) cell line.

Topics: Adenocarcinoma; Aged; Basement Membrane; Cell Adhesion; Cell Differentiation; Collagen; Culture Media, Serum-Free; Drug Combinations; Endometrial Neoplasms; Endometrium; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Lactoferrin; Laminin; Neoplasm Proteins; Proteoglycans; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

In the mouse uterus, lactoferrin is a major estrogen-inducible uterine secretory protein, and its expression correlates directly with the period of peak epithelial cell proliferation. In this study, we examine the expression of lactoferrin mRNA and protein in human endometrium, endometrial hyperplasias, and adenocarcinomas using immunohistochemistry, Western immunoblotting, and Northern and in situ RNA hybridization techniques. Our results reveal that lactoferrin is expressed in normal cycling endometrium by a restricted number of glandular epithelial cells located deep in the zona basalis. Two thirds (8 of 12) of the endometrial adenocarcinomas examined overexpress lactoferrin. This tumor-associated increase in lactoferrin expression includes an elevation in the mRNA and protein of individual cells and an increase in the number of cells expressing the protein. In comparison, only 1 of the 10 endometrial hyperplasia specimens examined demonstrates an increase in lactoferrin. We also observe distinct cytoplasmic and nuclear immunostaining patterns under different fixation conditions in both normal and malignant epithelial cells, similar to those previously reported in the mouse reproductive tract. Serial sections of malignant specimens show a good correlation between the localization of lactoferrin mRNA and protein in individual epithelial cells by in situ RNA hybridization and immunohistochemistry. Although the degree of lactoferrin expression in the adenocarcinomas did not correlate with the tumor stage, grade, or depth of invasion in these 12 patients, there was a striking inverse correlation between the presence of progesterone receptors and lactoferrin in all 8 lactoferrin-positive adenocarcinomas. In summary, lactoferrin is expressed in a region of normal endometrium known as the zona basalis which is not shed with menstruation and is frequently overexpressed by progesterone receptor-negative cells in endometrial adenocarcinomas.

Topics: Adenocarcinoma; Adult; Aged; Blotting, Northern; Cell Transformation, Neoplastic; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Immunohistochemistry; In Situ Hybridization; Ki-67 Antigen; Lactoferrin; Middle Aged; Neoplasm Proteins; Nitrosourea Compounds; Nuclear Proteins; Phenotype; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; Uterine Neoplasms

Topics: Adenocarcinoma; Animals; Breast Feeding; Colonic Neoplasms; Depression, Chemical; Diarrhea, Infantile; Endotoxins; Female; Humans; Immunity, Maternally-Acquired; Immunoglobulin A, Secretory; Infant, Newborn; Interleukin-6; Lactoferrin; Lipopolysaccharides; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred C3H; Milk, Human; Pregnancy; Spleen; Tumor Cells, Cultured; Weight Loss

Immunopathological analysis was made of phenotypic change in a recurrent parotid gland adenocarcinoma occurring in a patient with a long clinical course of 30 years or more. At the first and second operations, in 1959 and 1978, the resected parotid gland tumors were diagnosed histopathologically as acinic cell carcinoma. However, 11 years after the second operation, in 1989, the resected recurrent tumor showed a microscopically phenotypic change towards adenocarcinoma with typical tubular arrangement. At the last operation in 1991, histopathological examination of the tumor revealed adenocarcinoma with diffuse oncocytic change in association with cervical lymph node metastasis. These findings suggest that phenotypic change may occur in vivo among human neoplasms during a long period, which may be related to the cytodifferentiation in the salivary gland tumor.

Topics: Adenocarcinoma; Amylases; Carcinoembryonic Antigen; Carcinoma, Acinar Cell; Humans; Immunoenzyme Techniques; Immunohistochemistry; Lactoferrin; Microscopy, Immunoelectron; Muramidase; Parotid Neoplasms; Phenotype; Secretory Component

The immunohistochemical detection of lactoferrin was carried out with the PAP technique on pancreatic tissue samples of 23 patients, operated for acute (13) or chronic (4) pancreatitis as well as for adenocarcinomas (6). In order to control our immunohistochemical technique and the antisera produced by us we studied some tissue samples of human mammary gland and parotis. We detected lactoferrin in the glands of parotis and mammae as well as of their secretions. In the pancreatic tissue we found a positive reaction only in granulocytes of inflammatory areas with the exception of a luminal reaction on the surface of acinar cells in one case of pancreatic adenocarcinoma. We would like to interpret our results with the hypothesis of granulocytic origin of immunochemically detectable lactoferrin in the pancreatic juice of patients, especially in cases of chronic pancreatitis.

Topics: Adenocarcinoma; Adult; Aged; Breast; Female; Humans; Immunohistochemistry; Lactoferrin; Male; Middle Aged; Milk, Human; Pancreas; Pancreatic Neoplasms; Pancreatitis; Parotid Gland

Fifty-nine thyroid tumors were re-examined and studied using immunohistochemistry to detect the presence of ceruloplasmin (CP), lactoferrin (LF), thyroglobulin, thyrocalcitonin, carcinoembryonic antigen and ferritin. In an attempt to study the contribution of the immunodetection of CP and LF in the diagnosis of malignant versus benign tumors, specially in follicular tumors, we compared our results of immunodetection with those of Tuccari and Barresi, and carried out our own studies on the usefulness of these immunolabelling. Concerning CP and LF staining, we have found the following data: 1) little (in contrast to Tuccari and Barresi) or no staining in normal thyroid and benign adenomas; 2) diffuse and intense staining in papillary and follicular carcinomas (as noted by the previous authors); 3) diffuse and weak staining for medullary carcinomas (in contrast to Tuccari and Barresi who found none). Our findings suggest that a diffuse and intense cytoplasmic staining with CP and LF concerning more than one third of all cells is a criterion of malignancy, whereas a weak paranuclear staining of a few cells is more in favor of a benign process.

Topics: Adenocarcinoma; Adenoma; Biomarkers, Tumor; Carcinoma, Papillary; Ceruloplasmin; Humans; Immunohistochemistry; Lactoferrin; Neoplasm Proteins; Retrospective Studies; Sensitivity and Specificity; Thyroid Neoplasms

The expression of the haeme-binding protein, lactoferrin, was studied in human gastric tissues displaying normal, benign hyperplastic or malignant histology. A single 2.5-kb mRNA was detected in only 14% (2/14) of normal resections. This was similar to the finding that 85% of tumours were also negative, with 4/27 positive. In contrast, samples with superficial or atrophic gastritis had a high frequency of expression, with 5/7 and 9/14 positive respectively. The higher incidence of lactoferrin mRNA in antral samples was a reflection of the greater proportion of these compared with body resections of patients with gastritis. No expression was seen in any of 5 gastric carcinoma cell lines. High levels were observed in the cardia, in contrast to complete absence in the oesophagus. Immunocytochemistry showed localization of lactoferrin in cells of both antral and body glands. Chief cells, but not adjacent parietal cells, were strongly stained. In tissues exhibiting superficial or atrophic gastritis we observed a greater degree and intensity of staining as compared with samples with normal histology. We also observed some staining of tumour cells, though this was very patchy. Lactoferrin may have a role in mucosal iron transport in both normal and highly proliferating tissue, but does not appear to be significantly associated with malignant lesions.

Topics: Adenocarcinoma; Blotting, Northern; Cell Line; Gene Expression; Humans; Lactoferrin; RNA, Messenger; Stomach; Stomach Neoplasms; Tissue Distribution

The binding of 125I-lactoferrin to HT29-D4 cells, a clone of HT29 cells, was studied and compared to the binding of 125I-transferrin to the same cells. The binding of the two iron-transport proteins is saturable and reversible suggesting the presence of specific receptors for each protein. Scatchard analysis suggests the existence of binding sites for lactoferrin with the relatively high equilibrium dissociation constant, Kd1 of 408 nM. Additionally, the cell is capable of binding large amounts of lactoferrin with very low affinity, probably in a non-receptor intermediate fashion. The dissociation constant of transferrin and its receptor was calculated 9.29 nM which corresponds well to values found in the literature. In contrast to lactoferrin, the cell was capable of binding only low amounts of transferrin in a non-receptor intermediate fashion. After chemical crosslinking of lactoferrin to the cell surface, the radiolabeled lactoferrin was found in a complex of molecular mass 300 kDa. Crosslinking of transferrin resulted in a complex of much higher molecular mass. These data clearly show a binding site for lactoferrin different from the transferrin receptor. Only if competition experiments were performed with a high molar excess of both ligand proteins did a small percentage of either of the two ligands crossreact with the receptor for the other, possibly due to a structural similarity of the two glycoproteins.

Topics: Adenocarcinoma; Binding, Competitive; Humans; Lactoferrin; Lactoglobulins; Receptors, Cell Surface; Transferrin; Tumor Cells, Cultured

A total of 27 cases of salivary gland adenocarcinomas were studied from clinicopathological view point. Adenocarcinomas of the salivary gland were microscopically subclassified into 3 groups according to Luna's classification: Salivary duct carcinomas histologically resembled the ductal carcinoma of the breast, displayed nuclear atypia and had poorer prognosis than the other subclasses of salivary gland adenocarcinomas. Terminal duct carcinomas lacked in nuclear atypia and displayed a variety of growth patterns, including papillary, cribriform, tubular, and solid. Some terminal duct carcinomas showed prominent mucin-production. Epithelial-myoepithelial carcinomas had clear cytoplasms and exuberant glycogen. In addition to the clinicopathological study, nuclear areas of the tumor cells were measured in each of the 27 salivary gland adenocarcinomas, and mean nuclear area (MMA) and standard deviation (SD) were calculated. The group with more than 50 microns 2 of MNA had poorer prognosis than the group with 50 microns 2 or less of MNA, and the group with more than 13 microns 2 of SD had poorer prognosis than the group with 13 microns 2 or less of SD. Finally, immunohistochemical study was performed against various markers including keratin, epithelial membrane antigen, lactoferrin, S-100 protein, CEA, etc., using the Avidin-biotin-peroxidase complex method. Lactoferrin was present in most of the salivary duct carcinomas, on the other hand, S-100 protein was detected in all of the five cases of the terminal duct carcinoma investigated. But immunohistochemical study is not especially useful in distinguishing subclasses of salivary gland adenocarcinomas or investigating the origin of tumor cells.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Intraductal, Noninfiltrating; Cell Nucleus; Female; Humans; Immunoenzyme Techniques; Lactoferrin; Male; Middle Aged; Prognosis; S100 Proteins; Salivary Gland Neoplasms

Topics: Adenocarcinoma; Carcinoma, Papillary; Humans; Lactoferrin; Lactoglobulins; Thyroid Neoplasms

A clonal neoplastic epithelial duct cell (HSGc) of human salivary gland origin has a fine structure similar to the intercalated duct cell and the capacity to express secretory component and lactoferrin. HSGc cells tend to form an occasional glandular arrangement in vitro and in vivo, and transplantation of cells into nude mice resulted in production of adenocarcinoma. By repeated single cell cloning, different types of clones could be isolated from HSGc. Cuboidal clones resemble the parent cell, but fail to form the glandular arrangement or express lactoferrin, suggesting a less differentiated type. Elongated clones have a fine structure similar to myoepithelial cells and carry myoepithelial markers such as S100 protein, actin, and myosin which are not detected in the HSGc and its cuboidal clones. These myoepithelial-like clones are able to express secretory component, lactoferrin, and lysozyme and to produce glycosaminoglycans, suggesting that they are a functionally active form of the neoplastic cell but different from the normal myoepithelial cell. Judging from their growth properties in vitro and in vivo, the myoepithelial-like clones are less malignant than HSGc or its cuboidal clones. Of four elongated clones, two did not produce tumors in athymic mice, while all of the cuboidal clones were tumorigenic. These findings suggest a possible conversion of the neoplastic duct cell to myoepithelial-like variants with low malignancy.

Topics: Actins; Adenocarcinoma; Antigens; Carcinoma; Cell Cycle; Cell Line; Cell Separation; Clone Cells; Epithelium; Fluorescent Antibody Technique; Humans; Keratins; Lactoferrin; Microscopy, Electron; Muramidase; Myosins; S100 Proteins; Salivary Gland Neoplasms; Secretory Component

Presence of lysozyme, lactoferrin, alpha 1-antitrypsin, alpha 1-antichymotrypsin and ferritin was examined by the immunoperoxidase method in 15 consecutive parotid gland tumors as well as in normal parotid gland tissue. Lysozyme and lactoferrin were detected in intercalated duct cells of normal tissue and in the epithelial component of pleomorphic adenomas. alpha 1-antitrypsin, alpha 1-antichymotrypsin and ferritin were found in both epithelial and mesenchymal components of pleomorphic adenomas but not in normal parotid tissue. In the epithelial component of adenolymphoma only alpha 1-antichymotrypsin and lactoferrin were observed. The results would support a tentative histogenetic link between the intercalated duct cell and the epithelial component of the pleomorphic adenoma.

Topics: Adenocarcinoma; Adenolymphoma; Adenoma, Pleomorphic; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Chymotrypsin; Ferritins; Histocytochemistry; Humans; Immunoenzyme Techniques; Lactoferrin; Lactoglobulins; Muramidase; Parotid Neoplasms

Using immunoperoxidase procedures, the presence of lactoferrin was investigated in benign hypertrophy (40 cases), differentiated adenocarcinomas (20 cases) and undifferentiated carcinomas (10 cases) of the prostate. In benign hypertrophy, the glandular epithelium and the secretory product were consistently negative. Strong staining for lactoferrin was always observed in neoplastic cells of differentiated adenocarcinomas and in their endoluminal material; in contrast, a very slight positivity was noted in undifferentiated carcinomas. These findings are discussed in relation to the different degree of neoplastic glandular differentiation and functional activity of prostatic carcinomas.

Topics: Adenocarcinoma; Carcinoma; Histocytochemistry; Humans; Immunoenzyme Techniques; Lactoferrin; Lactoglobulins; Male; Prostatic Hyperplasia; Prostatic Neoplasms

Lactoferrin was examined for its effect on the growth of a human colon adenocarcinoma cell line (HT 29) in culture and its action was compared to that produced by transferrin and two different iron solutions (ferrous sulfate and ferric chloride). When transferrin was replaced by either iron solutions the cell grew in proportion to the quantity added and the maximal effect obtained was identical to that produced by transferrin alone. When transferrin was replaced by lactoferrin the cells were unable to proliferate for a long time. However, in the presence of low-concentration iron solutions, lactoferrin stimulated the cell growth, and the effect was more pronounced with the ferric chloride solution.

Topics: Adenocarcinoma; Cell Division; Cell Line; Chlorides; Colonic Neoplasms; Ferric Compounds; Ferrous Compounds; Humans; Kinetics; Lactoferrin; Lactoglobulins; Transferrin

Lactoferrin levels have been determined by radialimmunodiffusion in homogenates of both human benign prostatic hypertrophy obtained at open surgery from patients, some of whom had been treated with oestrogens or antiandrogens, and also in prostatic adenocarcinoma tissue removed by transurethral resection. Results show that in untreated benign prostatic hyperplasia there is a statistically lower lactoferrin level in the median compared with the lateral lobes. In patients with benign prostatic hypertrophy treated before prostatectomy with oestrogens or antiandrogens the lactoferrin concentration is decreased. In neoplastic tissue removed by open surgery, the lactoferrin level is very low. Homogenates of tissue resected from prostatic cancer patients show similarly low levels. The concentration of lactoferrin in human prostate is hormone dependent. The role of the protein is considered to be bacteriostatic.

Topics: Adenocarcinoma; Androgen Antagonists; Estrogens; Humans; Hyperplasia; Lactoferrin; Lactoglobulins; Male; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

Lactoferrin and lysozyme, parts of the non-specific defense system, were studied in normal and diseased parotid glands, using the immunohistochemical PAP-method. 31 normal and inflamed glands were investigated. The presence of lactoferrin and lysozyme was demonstrated in the acinar cells and some duct cells. The amount of these substances was increased in obstructive parotitis. The 52 carcinomas showed a distinct distribution pattern for lactoferrin (positive cases: adenocarcinomas 5 of 8; cystadenocarcinoma: 3 of 5; adenoid cystic carcinomas 2 of 4; salivary duct carcinomas 2 of 3). Some of the carcinomas in pleomorphic adenomas were positive for lactoferrin. Squamous cell carcinomas and anaplastic carcinomas were constantly negative. All carcinomas were negative for lysozyme. These observations are discussed with respect to their physiological and pathological significance.

Topics: Adenocarcinoma; Adenoma, Pleomorphic; Carcinoma; Carcinoma, Squamous Cell; Cystadenocarcinoma; Humans; Lactoferrin; Lactoglobulins; Muramidase; Parotid Neoplasms; Parotitis