pectins and Neoplasm-Metastasis

In this minireview, we examine the ability of modified citrus pectin (MCP), a complex water soluble indigestible polysaccharide obtained from the peel and pulp of citrus fruits and modified by means of high pH and temperature treatment, to affect numerous rate-limiting steps in cancer metastasis. The anti-adhesive properties of MCP as well as its potential for increasing apoptotic responses of tumor cells to chemotherapy by inhibiting galectin-3 anti-apoptotic function are discussed in the light of a potential use of this carbohydrate-based substance in the treatment of multiple human malignancies.

Topics: Animals; Anoikis; Antineoplastic Agents, Phytogenic; Apoptosis; Citrus; Galectin 3; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Pectins; Plant Extracts

This study intends to investigate the inhibitory potential of different plant derived saccharides on cell migration and adhesion of pancreatic ductal adenocarcinoma (PDAC) cells to microvascular liver endothelium, particularly considering the role of transmembranous galectin-3. PDAC cell lines PancTu1 and Panc1 were characterized by considerable (transmembranous) galectin-3 (Gal3) expression. SiRNA mediated Gal3 knockdown as well as treatment with differentially processed pectins and arabinogalactan-proteins (AGPs) did not impact on cell migration of either PDAC cell line. In contrast, Gal3 knockdown reduced adhesion of PDAC cells to the liver endothelial cell line TMNK-1 being more pronounced in Panc1 cells. Similarly, plant derived substances did not impact cell adhesion of PancTu1 cells while partially hydrolyzed citrus pectin (MCP), pectinase-treated MCP (MCP

Topics: Blood Proteins; Carcinoma, Pancreatic Ductal; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Citrus; Galectin 3; Galectins; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mucoproteins; Neoplasm Metastasis; Pancreatic Neoplasms; Pectins; Plant Proteins

Galectin‑3 is expressed in various tissues and plays an important role in the tumor microenvironment (TME). Galectin‑3 has been found to be overexpressed in a variety of cancers and is associated with tumor progression and metastasis. Over the past decades, emerging evidence has suggested that the TME may induce galectin‑3 expression to maintain cellular homeostasis and promote cell survival. Furthermore, galectin‑3 regulates immune cell function to promote tumor‑driven immunosuppression through several mechanisms. In the TME, intracellular and extracellular galectin‑3 has different functions. In addition, it has been reported that galectin‑3 is associated with glycolysis and mitochondrial metabolism in tumors, and it is involved in the regulation of relevant signaling pathways, thus promoting cancer cell survival via adapting to the TME. The aim of the present review was to summarize the current knowledge on galectin‑3 production and its function in the TME, its effect on TME immunosuppression, its association with tumor metabolism and relevant signaling pathways, and to report common types of cancer in which galectin‑3 is highly expressed, in order to ensure a comprehensive understanding of the critical effects of galectin‑3 on tumor progression and metastasis.

Topics: Animals; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Galectin 3; Glycolysis; Humans; Immune Tolerance; Mice; Mitochondria; Neoplasm Metastasis; Neoplasms; Pectins; Signal Transduction; Tumor Microenvironment

To examine the anti-metastatic activities of polysaccharides in broccoli, purified polysaccharides (BCE-I, -II, and -III) were isolated by fractionation of broccoli enzyme extracts and subsequent ethanol precipitation. BCE-I mainly consisted of galactose and arabinose, whereas BCE-II mainly consisted of galacturonic acid and rhamnose, and BCE-III mainly consisted of rhamnose and galactose. Of the three fractions, stimulation of murine peritoneal macrophages by BCE-I showed the greatest enhancement of tumor necrosis factor-α, interleukin (IL)-12, and IL-6 secretion. In addition, intravenous (i.v.) administration of BCE-I enhanced the lethal activity of natural killer (NK) cells on YAC-1 tumor cells significantly and dose-dependently in an

Topics: Animals; Antineoplastic Agents, Phytogenic; Brassica; Colonic Neoplasms; Female; Humans; Immunity, Innate; Interleukin-12; Interleukin-6; Killer Cells, Natural; Lung Neoplasms; Macrophage Activation; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Pectins; Plant Extracts; Polysaccharides

To investigate the antitumor and antimetastatic polysaccharide from the mature leaves of green tea, GTE-II was purified using size exclusion chromatography. GTE-II consisted of 15 different sugars including rarely observed sugars such as 2-O-methyl-fucose, 2-O-methyl-xylose, apiose, aceric acid, 3-deoxy-d-manno-2-octulosonic acid, and 3-deoxy-d-lyxo-2-heptulosaric acid, which were characteristics of pectic polysaccharide rhamnogalacturonan-II. Treatment of peritoneal macrophages with GTE-II not only increased interleukin (IL)-6 and IL-12 production, but also had significantly increased tumoricidal activity against Yac-1 tumor cells than those obtained from untreated mice. In an assay of natural killer (NK) cell activity, intravenous administration of GTE-II significantly stimulated NK cytotoxicity against Yac-1 tumor cells. Furthermore, the depletion of NK cells by injection of rabbit anti-asialo GM1 serum eliminated the inhibitory effect of GTE-II on B16BL6 melanoma cells. These data suggest that GTE-II inhibits tumor metastasis, and its antitumor effect is associated with activation of macrophages and NK cells.

Topics: Animals; Antineoplastic Agents; Female; Glycosylation; Killer Cells, Natural; Lung Neoplasms; Macrophage Activation; Melanoma, Experimental; Methylation; Mice; Neoplasm Metastasis; Pectins; Plant Leaves; Polygalacturonase; Tea

Corn pectic polysaccharide (COPP) inhibited galectin-3 mediated hemagglutination at Minimum Inhibitory Concentration (MIC) of 4.08 μg/mL as opposed to citrus pectin (25 μg/mL), a well known galectin-3 inhibitor and lactose (4.16 μg/mL)--sugar specific to galectin-3. COPP effectively (72%) inhibited invasion and metastasis in experimental animals. In vivo results were substantiated by modulation of cancer specific markers such as galectin-3, which is a key molecule for initiation of metastatic cascade, vascular endothelial growth factor (VEGF) that enhances angiogenesis, matrix metalloproteinases 2 and 9 that are required for invasion, NF-κB, a transcription factor for proliferative potency of tumor cells and a phosphoglucoisomerase (PGI), the activity of which favors cancer cell growth. Structural characterization studies indicate the active component (relatively less acidic, 0.05 M ammonium carbonate, 160 kDa fraction) which showed antimetastatic potency in vitro with MIC of 0.09 μg/mL, and ∼ 45 fold increase in the activity when compared to that of COPP. Gas liquid chromatographic analysis indicated the presence of rhamnose (1%), arabinose (20%), xylose (3%), mannose (4%), galactose (54%) and uronic acid (10%) in different proportions. However, correlative data attributed galectin-3 inhibitory activity to enhanced levels of arabinose and galactose. FTIR, HPLC and NMR spectroscopic analysis further highlights that COPP is an arabinogalactan with methyl/ethyl esters. It is therefore suggested that the blockade of galectin-3 mediated lung metastasis appears to be a result of an inhibition of mixed functions induced during metastasis. The data signifies the importance of dietary carbohydrate as cancer-preventive agent. Although pectin digestibility and absorption are issues of concern, promising in vivo data provides evidence for the cancer preventive property of corn. The present study reveals for the first time a new component of corn, i.e.,--corn pectin with cancer preventive activity apart from corn starch that has been in wide use for multipurpose health benefits.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Dietary Carbohydrates; Galactans; Galectin 3; Melanoma, Experimental; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Pectins; Polysaccharides; Vascular Endothelial Growth Factor A; Zea mays

A polysaccharide fraction, HBE-III, was successfully purified in a high yield (40.4%) from its crude polysaccharide (HBE-0) which was prepared from pectinase hydrolysates of the peels of the Korean Citrus Hallabong. In experimental lung metastasis studies of Colon 26-M3.1 carcinoma cells, prophylactic administration of HBE-III significantly inhibited lung metastasis in a dose-dependent manner. In an in vitro cytotoxicity analysis, HBE-III (up to 1000 μg/mL) did not affect the growth of Colon 26-M3.1 cells and normal cells. HBE-III enhanced production of IL-6 and IL-12 by murine peritoneal macrophages. In an assay for natural killer (NK) cell activity, HBE-III (1000 μg/mouse, i.v.) significantly augmented NK cytotoxicity against Yac-1 tumor cells. The depletion of NK cells by injection of mouse anti-asialo GM1 serum abolished the inhibitory effect of HBE-III on lung metastasis of Colon 26-M3.1 cells. These data suggest that HBE-III may inhibit tumor metastasis via activation of macrophages and NK cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line; Cell Line, Tumor; Citrus; Colon; Colonic Neoplasms; Female; Hydrolysis; Interleukin-12; Interleukin-6; Killer Cells, Natural; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Pectins; Polysaccharides

The aim of this study was to develop in situ gellable hydrogels composed of periodate oxidized citrus pectin (OP) for localized anticancer drug delivery and evaluate the potential of OP to inhibit cancer metastasis. Doxorubicin (Dox) was coupled to OP by imine bonds. Adipic dihydrazide (ADH) was used for cross-linking of the Dox-OP conjugates. The Dox-OP conjugate solution gelled within 2 min after addition of ADH. The release rate of Dox from the hydrogels was controllable by an additive amount of ADH. The released Dox retained anticancer activity. OP was shown to have a potency to prevent homotypic cancer cell aggregation compared to unmodified citrus pectin, strongly suggesting that OP released from hydrogels in vivo will inhibit cancer metastasis. These results indicate that OP hydrogels have the potential to prevent progression of primary cancer by the released Dox and generation of metastatic cancer by the released OP.

Topics: Antineoplastic Agents; Cell Aggregation; Cell Line, Tumor; Citrus; Doxorubicin; Drug Delivery Systems; Gels; Humans; Hydrogels; Neoplasm Metastasis; Neoplasms; Oxidation-Reduction; Pectins

In this report, we challenge a common perception that tumor embolism is a size-limited event of mechanical arrest, occurring in the first capillary bed encountered by blood-borne metastatic cells. We tested the hypothesis that mechanical entrapment alone, in the absence of tumor cell adhesion to blood vessel walls, is not sufficient for metastatic cell arrest in target organ microvasculature. The in vivo metastatic deposit formation assay was used to assess the number and location of fluorescently labeled tumor cells lodged in selected organs and tissues following intravenous inoculation. We report that a significant fraction of breast and prostate cancer cells escapes arrest in a lung capillary bed and lodges successfully in other organs and tissues. Monoclonal antibodies and carbohydrate-based compounds (anti-Thomsen-Friedenreich antigen antibody, anti-galectin-3 antibody, modified citrus pectin, and lactulosyl-l-leucine), targeting specifically beta-galactoside-mediated tumor-endothelial cell adhesive interactions, inhibited by >90% the in vivo formation of breast and prostate carcinoma metastatic deposits in mouse lung and bones. Our results indicate that metastatic cell arrest in target organ microvessels is not a consequence of mechanical trapping, but is supported predominantly by intercellular adhesive interactions mediated by cancer-associated Thomsen-Friedenreich glycoantigen and beta-galactoside-binding lectin galectin-3. Efficient blocking of beta-galactoside-mediated adhesion precludes malignant cell lodging in target organs.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Bone Neoplasms; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Citrus; Female; Galectin 3; Humans; Leucine; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Pectins; Prostatic Neoplasms

The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro.. In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test.. Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner.. MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Breast Neoplasms; Chemotaxis; Citrus; Colonic Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Endothelium, Vascular; Fluorescent Antibody Technique, Indirect; Galectin 3; Immunohistochemistry; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Pectins; Recombinant Proteins; Tumor Cells, Cultured; Umbilical Veins

Modified citrus pectin (MCP), also known as fractionated pectin, is a complex polysaccharide obtained from the peel and pulp of citrus fruits. Modified citrus pectin is rich in galactoside residues, giving it an affinity for certain types of cancer cells. Metastasis is one of the most life-threatening aspects of cancer and the lack of effective anti-metastatic therapies has prompted research on MCP's effectiveness in blocking metastasis of certain types of cancers, including melanomas, prostate, and breast cancers.

Topics: Citrus; Humans; Neoplasm Metastasis; Pectins; Structure-Activity Relationship

Prostate cancer is the most common cancer diagnosed in U.S. men and remains incurable once it has metastasized. Many stages of the metastatic cascade involve cellular interactions mediated by cell surface components, such as carbohydrate-binding proteins, including galactoside-binding lectins (galectins). Modified citrus pectin (pH-modified), a soluble component of plant fiber derived from citrus fruit, has been shown to interfere with cell-cell interactions mediated by cell surface carbohydrate-binding galectin-3 molecules.. The aim of this study was to determine whether modified citrus pectin, a complex polysaccharide rich in galactosyl residues, could inhibit spontaneous metastasis of prostate adenocarcinoma cells in the rat.. The ability of modified citrus pectin to inhibit the adhesion of Dunning rat prostate cancer MAT-LyLu cells to rat endothelial cells was measured by 51Cr-labeling. Modified citrus pectin inhibition of MAT-LyLu cell anchorage-independent growth was measured by colony formation in agarose. The presence of galectin-3 in rat MAT-LyLu cells and human prostate carcinoma was demonstrated by immunoblotting and immunohistochemistry. One million MAT-LyLu cells were injected subcutaneously into the hind limb of male Copenhagen rats on day 0. Rats were given 0.0%, 0.01%, 0.1%, or 1.0% (wt/vol) modified citrus pectin continuously in their drinking water (from day 4 until necropsy on day 30). The number of MAT-LyLu tumor colonies in the lungs were counted.. Compared with 15 or 16 control rats that had lung metastases on day 30, seven of 14 rats in the 0.1% and nine of 16 rats in the 1.0% modified citrus-pectin group had statistically significant (two-sided; P < .03 and P < .001, respectively) reductions in lung metastases. The lungs of the 1.0% modified citrus pectin-treated rats had significantly (two-sided; P < .05) fewer metastatic colonies than control groups (9 colonies +/- 4 [mean +/- SE] in the control group compared with 1 colony +/- 1 in the treated group). Modified citrus pectin had no effect on the growth of the primary tumors. In vitro, modified citrus pectin inhibited MAT-LyLu cell adhesion to rat endothelial cells in a time- and dose-dependent manner as well as their colony formation in semisolid medium.. We present a novel therapy in which oral intake of modified citrus pectin acts as a potent inhibitor of spontaneous prostate carcinoma metastasis in the Copenhagen rat.. Further investigations are warranted to determine the following: 1) the role of galectin-3 in normal and cancerous prostate tissues and 2) the ability of modified citrus pectin to inhibit human prostate metastasis in nude mice.

Topics: Adenocarcinoma; Administration, Oral; Analysis of Variance; Animals; Cell Adhesion; Cell Separation; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Humans; Immunoblotting; Immunoenzyme Techniques; Male; Neoplasm Metastasis; Pectins; Prostatic Neoplasms; Rats; Tumor Stem Cell Assay

Modified citrus pectin (MCP) added to the media of cultured androgen-independent human prostatic JCA-1 cells reduced cell growth and correspondingly [3H]thymidine incorporation into DNA, which was correlated with the down-regulation of cyclin B and p34cdc2 MCP also induced distinct increases in specific endogenous phosphoproteins, including a cAMP-stimulated 52,000 (52-kDa) protein. Since metastatis has been inversely correlated with nm23 gene expression in some cancer cells and was reportedly inhibited by MCP in a rat prostate model, we investigated steady state level changes in the nm23 protein in JCA-1 cells and found it to be unexpectedly suppressed as a result of exposure to MCP.

Topics: Animals; CDC2 Protein Kinase; Cell Division; Citrus; Cyclin D; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasm Metastasis; Pectins; Phosphoproteins; Prostatic Neoplasms; Proto-Oncogene Proteins; Rats; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Topics: Adult; Aged; Alginates; Animals; Arthritis, Rheumatoid; Carcinoma; Cattle; Female; Hodgkin Disease; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Hydrogen-Ion Concentration; Leukemia; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pectins; Polysaccharides; Synovial Fluid; Time Factors; Viscosity