Metastasis (Met) largely contributes to the major cause of cancer deaths throughout the world, rather than the growth of the tumor mass itself. The present report brings together several of the pertinent contributors to cancer growth and metastatic processes from an activity standpoint. Such biological activities include the following: (1) cell adherence and detachment; (2) cell-to-cell contact; (3) contact inhibition; (4) the cell interfacing with the extracellular matrix (ECM); (5) tumor cell-to-stroma communication networks; (6) chemotaxis; and (7) cell membrane potential. Moreover, additional biochemical factors that contribute to cancer growth and metastasis have been shown to comprise the following: (a) calcium levels in the extracellular matrix and in intracellular compartments; (b) cation voltage and ATP-regulated potassium channels; (c) selective and non-selective cation channels; and (d) chemokines (cytokines) and their receptors, such as CXCL12 (SDF-1) and its receptor/binding partner, CXCR4. These latter molecular components represent a promising group of an interacting and synchronized set of candidates ideal for peptide therapeutic targeting for cancer growth and metastasis. Such peptides can be obtained from naturally occurring proteins such as alpha-fetoprotein (AFP), an onco-fetal protein and clinical biomarker.

Objectives and AimsThe objectives in the present report comprise several in number.First, the integrin biologic functions and activities are described.Second, the types and family members of the heterodimeric celladhesion integrin molecules are discussed on an overview fashion.Third, naturally occurring peptides derived from "mother" proteins will be addressed as integrin-like peptidomimetics.Finally, a prime example of an integrin-like non-toxic peptide mimetic is described which displays activities such as inhibition of platelet aggregation, suppression of cell-to-matrix adhesion, cell migration/spreading, and cell-to-cell contact activities. C) The Integrin Cell Surface ReceptorsThe integrin superfamily of cell surface receptors consists of hetero-dimeric (alpha and beta chains) transmembrane glycoproteins that mediate cell-to-extracellular matrix (ECM), adhesion, and cell-to-cell contact interactions [10,11].The integrins are integral cell surface single pass-transmembrane receptors consisting of two paired chains of non-covalently linked alpha and beta polypeptide chains.Both integrins and the ECM molecules play important roles in ontogenetic development, maintenance of adult cell physiology, tissue repair, hyperplastic growth, hemostasis, and tumor oncogenesis [12][13][14].The dimeric hetero-complexed integrins further serve as cell membrane receptors capable of forming focal adhesion contact linkages to the cytoskeleton; such links are located on the inner AbstractIntegrins constitute a group of dimeric polypeptide chains that function as natural agonists of cell surface receptor-dependent cell activities.The integrins themselves comprise a superfamily of hetero-dimeric (alpha and beta chains) transmembrane cell surface receptors whose functions include cell adhesion, growth, migration, and angiogenesis.In comparison, the integrin-like peptides (ILP) comprise groups of protein derived segments, namely, short peptides derived from naturally occurring proteins from intrinsic subdomain fragments or short motifs present on larger proteins or enzymes.Certain ILPs can bind or compete for amino acid sequence sites located on integrin beta-1 and beta-3 chains of heterocomplex receptors.Binding at major sites or allosteric minor sites can inhibit or block cell migration, angiogenesis, metastasis, and platelet aggregation.Recently, a small integrin-like peptide derived from naturally occurring alpha-fetoprotein (AFP), similar to a disintegrin, has been reported to inhibit growth and adhesion functions associated with integrin-dependent cell activities.The present report describes an example of an AFP integrin-like peptide and lends credence to support its proposed use in adjunct cancer therapies.

Growth Inhibitory Peptide (GIP) is an alpha-fetoprotein (AFP) derived peptide found during human pregnancy, which gradually disappears following childbirth in both the woman and the newborn. Following a stress-induced conformational change in the AFP molecule, GIP is exposed on the protein surface from a concealed occult site on the unfolded full-length AFP. The exposed 34-amino acid GIP peptide then targets, blocks, and suppresses malignant growth in the mammalian body. In the present report, GIP has been demonstrated to inhibit cell growth in vitro in nine different types of cancers including breast, prostate, and ovarian among others. GIP can further assist in preventing blood clotting, arresting growth via the cytoplasmic growth cycle, suppressing tumor blood vessel angiogenesis, and inhibiting circulating cancer cell metastasis. In further studies, GIP has been reported to suppress cancer growth in 38 of 60 different cancer cell culture lines. The growth suppressed human breast cancer cell lines included MCF-7, T-47D, Bt-547, MDA-MB-231, MDA-MB-435, in addition to mouse mammary tumor implants and xenografts. Thus, GIP was found to suppress and inhibit cancer growth in both in vitro and in vivo preclinical studies.

The various immunological roles of human alpha-fetoprotein (HAFP) and its correlation with hepatomas, i.e., hepatocellular carcinomas (HCCs), are not always addressed together in the biomedical literature even though HAFP has long been utilized as a biomarker for hepatomas. Although the well-being of the newborn, infant, and juvenile can be monitored by the measurement of age-dependent HAFP in biological fluid levels throughout these stages, the majority of clinical reports in these age groups do not include hepatomas (except hepatoblastomas) because of their later onset. However, reports concerning the interaction of HAFP and immune-associated proteins and cells in HCC patients in both applied clinical research and investigational settings has gradually increased over the years; thus ,it has expanded our base knowledge of mounting an immunotherapeutic response against AFP in hepatomas. The different immune-associated proteins (cytokines, chemokines, interleukin, kinins) interacting with HAFP has remained less reported due to limitations of appropriate in vitro and in vivo models. Concomitantly, the advances in elucidating the various immunological activities of AFP are opening new vistas of knowledge regarding the physiological roles of AFP in the growth of HCC. The present review surveys HAFP as an immunologic response modifier and regulator for HCC and its use in the generation of AFP – sensitized lymphocytes. An attempt is also made to relate the AFP activities to HCC progression following immunotherapies. Hence, the present review was divided into two major sections; I) AFP structure and homologies in the immune response, and II) the therapeutic use of AFP in HCC patients in adult stages in both in vivo and in vitro models

The serum carrier/ transport function of mammalian alpha-fetoproteins (AFP) has long been known in the biomedical literature.Many published reports of AFP biological activities have noted in their introductory remarks that AFP is capable of binding, transporting, and delivering cargo ligands to many cells and tissues of the body.AFP, similar to albumin, can bind a multitude of ligands including fatty acids, steroids, drugs, and heavy metals.However, in lieu of the vast array of diverse ligands transported by AFP, the biomedical literature is devoid of a complete reference source detailing a listing, enumeration, classification, and description of all known ligands bound and transported by AFP.Unknowingly, there exists an umet need for a published review that has compiled all known ligands that bind AFP, together with their binding affinities and number of binding sites.The present review represents an attempt to provide a single reference source which could serve as a compendium of all known ligands that bind to mammalian AFP.Surprisingly, these ligands were found to number nearly 50 different biochemical compounds.The present comprehensive survey was designed to include ligands such as; non-esterified poly-unsaturated fatty acids, estrogens, dyes, toxins, flavonoids, phytoestrogens, commercial drugs, synthetic estrogens, heavy metals, retinoids, thyroid hormones, and plant/insect lectin agglutinins.

Alpha-fetoprotein (AFP) has long been associated with regulation and modulation of the immune system in a variety of mammals. In the last several decades, AFP has been linked to autoimmune diseases (ADs) during both pregnancy and in non-gestational disorders via an immunomodulatory function. The course of ADs are highly influenced by soluble factors such as cytokines, chemokines, interleukins, hormones, kinins, growth factors, proteins such as AFP, and various T-cells generated from the immune response. Such factors appear to serve as protective or ameliorating agents during the induction effector stages of the immune response. Immunomodulatory activities of AFP are known to affect: 1) induction of T-cell suppressor activity; 2) down-regulating dendritic-like cell antigen expression; and 3) impairing the function of macrophages and T-cells. Some factors may even be involved in blocking the rejection of the embryo/fetus as an allograft in the mother at the initiation of pregnancy. Thus, the present report reviews the immunomodulation function of AFP during the course of autoimmune disease utilizing AD disorders such as: myasthenia gravis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune liver disorders, diabetes, thyroiditis, and others.

Human alpha-fetoprotein (AFP) is well-known as the “gold standard” biomarker for liver and germ cell tumors. It has also been utilized as a pregnancy screening analyte for neural tube defects as well as Down syndrome, when combined with other gestational-age dependent biomarkers. However, a lesser known and recognized property of AFP is its role in the maintenance and monitoring of fetal growth during ontogenetic development in man. Although a major function of AFP during pregnancy involves the serum transport of estrogens, fatty acids, retinoid, and other compounds, the positive and negative regulation of fetal growth is a vital additional function of AFP. Human AFP largely functions as a growth promoting agent; however, the fetal protein is able to temporarily convert to a growth inhibitory factor in stress and shock environments in the fetal milieu. The development of a transient form of AFP or its derived peptides could be harnessed for use as an adjunct therapeutic agent to treat cancer in adults.

Failure of immune tolerance leads to production of autoantibodies to self-antigens. The repertoire of autoantibodies detected in cancer patients can indicate the presence of autoimmune disease. Alpha-fetoprotein (AFP) autoantibodies have been found in patients with hepatocellular carcinoma (HCC) and in juvenile Batten disease (BD), a neurodegenerative condition involving autoimmunity. Variant conformational forms of AFP together with exposed occult antigenic determinant sites on the AFP polypeptide resemble the features of a disordered protein which can impair central immune tolerance. These aberrant structural protein forms can lead to the persistence of autoantibody production by immune sensitized B-lymphocytes. Thus, it is not surprising that AFP, a self-antigen, can induce autoimmune responses in humans. Herein, we discuss the molecular and antigenic properties of AFP which make it a disordered protein, and its ability to induce autoantibody production to AFP cryptic epitopes in both HHC and BD patients. Such insights might aid in the future design of AFP-based vaccines and to discovery of novel pathogenic mechanisms of autoimmune diseases which demonstrate the presence of denatured intermediate forms of AFP.

Breast cancer (BC) is the leading cause of cancer-related deaths in women worldwide. However, the majority of cancer mortalities can be attributed to cancer cell metastasis to distal organs/tissues rather than the primary tumor mass itself. The microenvironment surrounding the main tumor mass, as well as its final migration destination, plays a crucial role in the survival, growth, proliferation, and progression of BC. Intercellular stromal cells and components of the microenvironment surrounding a tumor comprise a nurturing cubicle that provides a communication network of cross-talk and signaling between the tumor cells and the extracellular matrix (ECM) and interstitial cells. This network connection enables the tumor cells to engage in metastatic-associated activities such as cell adhesion, invasiveness, mobility, migration, cell shape change, cell-to-cell contact, and basement membrane degradation. An untapped therapeutic approach that might disable the communication network between cancer and stromal cells could possibly aid in providing this unmet need in treating metastatic disease. The intravenous administration of select protein-derived peptides to patients might have the potential to occupy, saturate, and block receptors and binding proteins at the interstitial/ECM communication interface with tumors.

Breast cancer (BC) is the leading cause of cancer-related deaths in young to middle-aged women worldwide. Moreover, the survival rate in BC-patients is only 20% when associated with metastatic disease. The high mortality rate observed in BC women with metastatic disease has precipitated a major challenge revealing an unmet need to develop new therapeutic strategies in treating metastatic cancer. One such approach has involved utilization of chemokines and their receptors as therapeutic targets for cancer metastasis. It has been established that a definitive correlation exists between overexpressed CXCR4 malignant cell receptors and cancer cell growth, invasion, and migration. It is also widely accepted that the CXCR4 receptor, complexed to its CXCL12 ligand, plays a major role in establishing migratory pathway gradients for cancer cells migrating to distant tissues/organ sites. It would follow that chemokine decoy ligands, such as peptide antagonists and inhibitors, could serve to induce receptor blockade and impede subsequent intracellular signaling. Such ligands, synthetic and natural, reportedly contribute to reducing cancer cell growth, invasion, adherence, and migration. The present commentary describes several existing synthetic CXCR4 receptor-ligand peptide antagonists and presents a strategy to develop naturally-occurring human protein-derived peptide candidates.

Gastric (stomach) cancer (GC) is the fourth leading cause of cancer deaths worldwide.Alpha-fetoprotein (AFP) secreting gastric cancer (AFP(+) GC represents an aggressive, less common subtype of stomach cancer exhibiting poor prognosis, low patient survival times, high progression rates, and liver metastases.No standard treatment regimen is presently in practice although multimodal therapies have been employed, while some drug resistance has been encountered in chemotherapy.AFP(+)GC is known to be more lethal than AFP-nonsecreting tumors with a patient median survival time of only 14 months.The reason for the increased mortality and morbidity of AFP-secreting GC has not been completely understood although multiple factors have been forwarded.Such factors include later stage diagnosis, unresectable metastases, rapid tumor growth, high mitotic rates, and elevated cellular expression of growth-promoting proteins.However, in recent years, a better understanding of the physiological (biological) activities of AFP as a growth regulatory cell-signaling factor have emerged.Such studies have established that AFP itself, acting through a cell surface receptor, is a potent tumor growth promoter as demonstrated in the present report.

The cell uptake and trans-passage of alpha-fetoprotein (AFP) through the cytoplasm has long been reported in the literature in a progressive albeit piecemeal fashion. However, recent novel immunohistochemical studies have provided valuable new insights into the intra-cytoplasmic fate of endocytosed AFP in various cells including cancer and immune-responsive cells. Employing biochemical inhibitors and antibodies to various endosomal and cytoskeletal-related proteins and enzymes, investigators have tracked in detail the organelle pathway from AFP cell uptake to its final intracellular compartmental destination. These added contributions highlight and contrast two different cytoplasmic trans-passage routes for AFP. One pathway involves endosomal vesicular transport of AFP free of ligands, while the other route consists of ligand-bound (fatty acids/steroids) AFP as a component of an in-and-out cell shuttle system. Finally, the present commentary distinguishes between antigen-presenting dendritic cells employing the scavenger mannose receptor (CD206), and hepatoma (HEPG2) cells utilizing the CD36, LOX-1, and SRB1 scavenger receptors.

The Journal of Cancer Metastasis and Treatment is an open access journal focused on cancer metastasis and treatment, including the occurrence, development, progression, metastasis, and treatment of oncologic disease. It covers basic, translational and clinical research related to cancer cell biology, genomics, precision medicine, oncology internal medicine, radiotherapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neurooncology, etc.

Although much has been published on the domain structures of human alpha-fetoprotein (AFP), the AFP third domain (AFP-3D) has emerged as an important fragment regarding the binding, docking, and interaction sites for hydrophobic ligands, multiple receptors, ion channels, and cell cycle proteins. In keeping with previous reports, studies have shown beyond doubt that certain amino acid (AA) sequences on AFP-3D provide a docking interface for protein-to-protein interactions (complexing) for such proteins. By means of a computer software program designed to study such “in silico” interactions, certain AA sequences on AFP-3D were identified which could plausibly interact with a group of DNA damage-sensing and repair (DDSR) proteins. The DDSR proteins identified included: 1) BRCA1 and BRCA2 2) FANC1 and FANCD2 3) nibrin 4) ATM and ATR and 5) DNA-PK kinase. Following the mapping of the AFP-3D with DDSR protein interaction sites, the computer-derived AFP-AA identification sequences were examined for similarities and comparisons to previously reported ligand, receptor, channel and other protein interaction sites on AFP-3D. Literature searches revealed that the association of AFP with the DDSR proteins showed correlations not only with clinical serum AFP levels, but also with an intracytoplasmic nonsecreted form of AFP, which interacts with transcription factors, cell death (apoptosis) proteins, nuclear receptors, and enzymes (caspases). The DDSR proteins that interacted with AFP were also found to be involved with cell cycle checkpoint proteins, cyclins and their dependent kinases, and ubiquitin ligases. Finally, both the clinical and experimental reports on the AFP-3D association with DDSR proteins were consistent with the “in silico” findings of this report.

Breast cancer and Alzheimer's disease (AD) are major causes of death in older women. Interestingly, breast cancer occurs less frequently in AD patients than in the general population. Amyloidosis, the aggregation of amyloid proteins to form amyloid bodies, plays a central role in the pathogenesis of AD and other human neuropathies by forming intracellular fibrillary proteins. Contrary to popular belief, amyloidosis is a common occurrence in mammalian cells, and has recently been reported to be a natural physiological process in response to environmental stress stimulations (such as pH and temperature extremes, hypoxia, and oxidative stress). Many proteins contain an intrinsic "amyloid-converting motif", which acts in conjunction with a specific noncoding RNA to induce formation of proteinaceous amyloid bodies that are stored in intracellular bundles. In cancer cells such as breast and prostate, the process of amyloidosis induces cells to enter a dormant or resting stage devoid of cell division and proliferation. Therefore, cancer cells undergo growth cessation and enter a dormant stage following amyloidosis in the cell; this is akin to giving the cell AD to cease growth.

Alpha-fetoprotein (AFP) is a 69 kD fetal-and tumor-associated single-chain glycoprotein belonging to the albuminoid gene family. AFP functions as a carrier/transport molecule as well as a growth regulator and has been utilized as a clinical biomarker for both fetal defects and cancer growth. Lysophospholipids (LPLs) are plasma membrane-derived bioactive lipid signaling mediators composed of a small molecular weight single acyl carbon chain ( palmitic, oleic acid) attached to a polar headgroup; they range in molecular mass from 250-750 daltons. The LPLs consist of either sphingosine-1-phosphate or lysophosphatidic acid, and mostly their choline, ethanolamine, serine or inositol derivatives. They are present only in vertebrates. These bioactive paracrine lipid mediators are ubiquitously distributed in tissues and are released from many different cell types ( platelets, macrophages, monocytes, etc.)involved in developmental, physiological, and pathological processes. The LPLs bind to four different classes of G-protein coupled receptors described herein which transduce a multiple of cell effects encompassing activities such as morphogenesis, neural development, angiogenesis, and carcinogenesis. The identification of potential binding sites of LPL receptors on the AFP third domain receptor binding fragment was derived by computer modeling analysis. It is conceivable, but not proven, that AFP might bind not only to the LPL receptors, but also to LPLs themselves since AFP binds medium and long chain fatty acids. It is proposed that some of the activities ascribed to AFP in the past might be due in part to the presence of bound LPLs and/or their receptors.

Many cancer cells exhibit an unstable genome resulting from chromosomal aberrations and gene mutations in somatic cells which generate heterogeneous cell populations manifesting diseases such as cancer.Genomic/chromosomal instability can arise from non-repaired broken DNA along the chromosome or from loss of telomeric ends of chromosomes.Normally, DNA single or double-stranded breaks are repaired prior to the cells' entrance into the mitotic phase of the cell cycle.This progressive passage is overseen by DNA-damage sensors, checkpoint proteins, and kinase enzymes at each cyclic phase transition point.However, some cancer cells exhibit escape behaviors to evade checkpoint surveillance networks during cell cycle progression.Examples of human diseases associated with DNA-associated disorders can be found in ataxia telangiectasia (AT), Fanconi's anemia (FA), immunodeficiency disorders, and others.Serum alpha-fetoprotein (AFP) levels have been reported as abnormal in these and other DNA/ chromosome instability disorders; in such situations, AFP appears to reflect the presence of impaired DNA damage and repair networks in certain cells.Although serum AFP presently serves as a biomarker in multiple disorders and diseases such as liver cancer and teratomas, the present discourse suggests that AFP might further serve as a reporter protein for the presence of DNA-damage sensing and repair networks in precancerous transforming cells.

Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability disorders which lack the capability to repair DNA breaks. The lesion occurs at a checkpoint regulatory step of the G2 to mitotic transition, allowing FA cells to override cell-cycle arrest. FA DNA repair pathways contain complementation groups known as FANC proteins. FANC proteins form multi-protein complexes with BRCA proteins and are involved in homologous DNA repair. An impaired cascade in these events imparts an increased breast cancer susceptibility to female FA patients. Elevations of sAFP have availed this fetal protein to serve as a biomarker for FA disease. However, the origin of the synthesis of sAFA has not been determined in FA patients. We hypothesize that hematopoietic multipotent progenitor stem cells in the bone marrow are the source of sAFP production in FA patients.

The carboxy-terminal third domain of alpha-fetoprotein (AFP-3D) is known to harbor binding and/or interaction sites for hydrophobic ligands, receptors, and binding proteins. Such reports have established that AFP-3D consists of amino acid (AA) sequence stretches on the AFP polypeptide that engages in protein-to-protein interactions with various ligands and receptors. Using a computer software program specifically designed for such interactions, the present report identified AA sequence fragments on AFP-3D that could potentially interact with a variety of cell cycle proteins. The cell cycle proteins identified were (1) cyclins, (2) cyclin-dependent kinases, (3) cell cycle-associated proteins (inhibitors, checkpoints, initiators), and (4) ubiquitin ligases. Following detection of the AFP-3D to cell cycle protein interaction sites, the computer-derived AFP localization AA sequences were compared and aligned with previously reported hydrophobic ligand and receptor interaction sites on AFP-3D. A literature survey of the association of cell cycle proteins with AFP showed both positive relationships and correlations. Previous reports of experimental AFP-derived peptides effects on various cell cycle proteins served to confirm and verify the present computer cell cycle protein identifications. Cell cycle protein interactions with AFP-CD peptides have been reported in cultured MCF-7 breast cancer cells subjected to mRNA microarray analysis. After 7 days in culture with MCF-7 cells, the AFP-derived peptides were shown to downregulate cyclin E, SKP2, checkpoint suppressors, cyclin-dependent kinases, and ubiquitin ligases that modulate cyclin E/CdK2 transition from the G1 to the S-phase of the cell cycle. Thus, the experimental data on AFP-CD interaction with cell cycle proteins were consistent with the "in silico" findings.