leukotriene-b4 and Breast-Neoplasms

Oncogenic PIK3CA mutations (PIK3CA. The results emphasize that PIK3CA

Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Immunosuppressive Agents; Leukotriene B4; Myeloid-Derived Suppressor Cells; Phosphatidylinositol 3-Kinases; Tumor Microenvironment

RanBPM is a scaffolding protein that regulates several cellular processes by interacting with various proteins. Previously, we reported that RanBPM acts as a negative regulator of BLT2, a low-affinity leukotriene B

Topics: Adaptor Proteins, Signal Transducing; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cytoskeletal Proteins; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Leukotriene B4; MCF-7 Cells; Neoplasm Invasiveness; Nuclear Proteins; Reactive Oxygen Species; Receptors, Leukotriene B4

Leukotriene B4 (LTB4) is a potent pro-inflammatory eicosanoid that is derived from arachidonic acid, and its signaling is known to have a tumor-promoting role in several cancer types. In this study, we investigated whether enhanced LTB4 signaling confers resistance to the cytostatic transforming growth factor-β1 (TGF-β1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-β1-induced cell cycle arrest and expression of p15INK4B and p27KIP1. Mechanism study revealed that LTB4-mediated suppression of TGF-β1-induced Smad3 activation and growth inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L) through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species (ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling cascade. Furthermore, the LTB4/BLT1 signaling pathway leading to pSmad3L was constitutively activated in breast cancer cells and was correlated with TGF-β1-resistant growth of the cells in vitro and in vivo. In human breast cancer tissues, the expression level of pSmad3L (Thr179) had a positive correlation with BLT1 expression. Collectively, our data demonstrate for the first time that the induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a key mechanism by which LTB4 blocks the anti-proliferative responses of TGF-β1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Female; Hep G2 Cells; Humans; Leukotriene B4; Mice; Mice, Inbred BALB C; Mice, Nude; Mink; NADPH Oxidases; Phosphatidylinositol 3-Kinase; Phosphorylation; Reactive Oxygen Species; Receptors, Leukotriene B4; RNA Interference; Signal Transduction; Smad3 Protein; Time Factors; Transfection; Transforming Growth Factor beta1; Xenograft Model Antitumor Assays

To investigate the endogenous signaling pathways associated with high proliferation potential of breast cancer cells.. Breast cancer cell lines LM-MCF-7 and MCF-7 with high and low proliferation capability were used. The promoter activity of fatty acid synthase (FASN) was examined using luciferase reporter gene assay. The expression level of FASN mRNA was measured using RT-PCR and real time PCR, respectively. The level of leukotriene B4 (LTB4) was determined with ELISA. The expression levels of 5-lipoxygenase (5-LOX) was analyzed using RT-PCR and Western blot, respectively. 5-Bromo-20-deoxyuridine (BrdU) incorporation assay was used to study the proliferation of LM-MCF-7 and MCF-7 cells.. The promoter activity of FASN was significantly higher in LM-MCF-7 cells than MCF-7 cells. Treatment of LM-MCF-7 cells with ERK1/2 inhibitor PD98059 (30-50 μmol/L) or LOX inhibitor NDGA (25 μmol/L) abolished the activation of FASN. Moreover, treatment of LM-MCF-7 cells with the specific 5-LOX inhibitor MK-886 (20-40 μmol/L) or 5-LOX siRNA (50-100 nmol/L) decreased the promoter activity of FASN. The level of LTB4, the final metabolite produced by 5-LOX, was significantly higher in LM-MCF-7 cells than MCF-7 cells. Administration of exogenous LTB4 (1-10 nmol/L) was able to stimulate the promoter activity of FASN in MCF-7 cells. Treatment of LM-MCF-7 cells with the FASN inhibitor cerulenin (10 μmol/L) reduced all the levels of p-ERK1/2, 5-LOX, and LTB4. Treatment of LM-MCF-7 cells with cerulenin, PD98059, or MK-886 abolished the proliferation. Administration of exogenous LTB4 (10 nmol/L) significantly increased BrdU incorporation in MCF-7 cells.. THESE results suggest a novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN contributes to the sustaining growth of breast cancer LM-MCF-7 cells.

Topics: Arachidonate 5-Lipoxygenase; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cerulenin; Fatty Acid Synthases; Fatty Acid Synthesis Inhibitors; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Humans; Leukotriene B4; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Promoter Regions, Genetic; RNA, Small Interfering; Signal Transduction

Leukotriene B4 (LTB4) is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity LTB4 receptor, is significantly upregulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated in a BLT2-dependent manner in these breast cancer cells, suggesting that 'Nox1-derived ROS' lie downstream of BLT2. Consistent with the proposed role of 'Nox1-ROS' in pro-survival signaling, knockdown of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the 'BLT2-Nox1-ROS'-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.

Topics: Breast Neoplasms; Cells, Cultured; Female; Humans; Leukotriene B4; NADPH Oxidase 1; NADPH Oxidases; Reactive Oxygen Species; Receptors, Estrogen; Receptors, Leukotriene B4; Signal Transduction; Tetrazoles

Pomegranate fruit extracts (PFEs) possess polyphenolic and other compounds with antiproliferative, pro-apoptotic and anti-inflammatory effects in prostate, lung, and other cancers. Because nuclear transcription factor-kB (NF-kB) is known to regulate cell survival, proliferation, tumorigenesis, and inflammation, it was postulated that PFEs may exert anticancer effects at least in part by modulating NF-kB activity.. The authors investigated the effect of a novel, defined PFE consisting of both fermented juice and seed oil on the NF-kB pathway, which is constitutively active in aggressive breast cancer cell lines. The effects of the PFE on NF-kB-regulated cellular processes such as cell survival, proliferation, and invasion were also examined.. Analytical characterization of the bioactive components of the PFE revealed active constituents, mainly ellagitannins and phenolic acids in the aqueous PFE and conjugated octadecatrienoic acids in the lipid PFE derived from seeds.The aqueous PFE dose-dependently inhibited NF-kB-dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression.. Inhibition of motility and invasion by PFEs, coincident with suppressed RhoC and RhoA protein expression, suggests a role for these defined extracts in lowering the metastatic potential of aggressive breast cancer species.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dinoprostone; Female; Fruit; Gene Expression; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lythraceae; Neoplasm Invasiveness; NF-kappa B; NF-kappa B p50 Subunit; Phytotherapy; Plant Extracts; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; rhoC GTP-Binding Protein; Transcription Factor RelA

Neutrophil migration is a key host event against infection. Chemotherapy may alter neutrophil function and favor increased risk of infection. Herein, we investigated the effect of chemotherapy on the migration capacity of circulating neutrophils obtained from breast cancer patients and mechanisms involved in this event. Breast cancer women (n=23) at disease stage I-III and healthy control women (n=25) were prospectively enrolled. No differences in the in vitro migratory responses towards the chemotactic stimuli N-formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP), leukotriene B(4) (LTB(4)) and interleukin (IL)-8 were observed in purified neutrophils from controls and patients, in a microchemotaxis chamber assay. However, the migration capacity evaluated upon chemotherapy (5-fluoruracil, adriamycin and cyclophosphamide, 21-day intervals between cycles, total leukocyte count >/=2,000/mm(3)), on the day immediately before the beginning of the sixth cycle, showed that patient neutrophils (n=14) failed to migrate in response to fMLP compared to response observed upon diagnosis. Considering patients (n=8) with documented bacterial infection between cycles, the number of migrated neutrophils (mean+/-SD) compared to response at diagnosis was markedly reduced upon chemotherapy to either fMLP (30.1+/-8.26 vs. 2.81+/-1.28) or LTB(4) (15.72+/-4.8 vs. 2.8+/-1.64) stimuli respectively. Treatment of control neutrophils with sera of chemotherapy-treated patients with infective episodes, to test for the presence of circulating immunosuppressive factors, significantly reduced the migratory capacity of healthy neutrophils to fMLP, LTB(4) and IL-8, in a dose-dependent way. But no significant differences were found in the serum levels of nitric oxide (NO) metabolites, tumor necrosis factor (TNF)-alpha, IL-6, IL-8 and IL-10 collected at the same time as the collection of blood for neutrophil migration experiments. In conclusion, breast cancer patients showed suppressed neutrophil migratory response upon chemotherapy, accompanied by bacterial infection episodes. Circulating factors are involved, at least partially, in the inhibitory mechanism on neutrophil migration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Case-Control Studies; Cell Movement; Chemotaxis, Leukocyte; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Count; Leukotriene B4; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neoadjuvant Therapy; Neutrophils; Nitric Oxide; Prospective Studies; Tumor Necrosis Factor-alpha

The relationship between growth and alterations in arachidonic acid (AA) metabolism in human breast (MCF-7) and colon (SW480) cancer cells was studied. Four different fatty acid preparations were evaluated: a mixture of conjugated linoleic acid (CLA) isomers (c9,t11, t10,c12, c11,t13, and minor amounts of other isomers), the pure c9,t11-CLA isomer, the pure t10,c12-CLA isomer, and linoleic acid (LA) (all at a lipid concentration of 16 microg/mL). 14C-AA uptake into the monoglyceride fraction of MCF-7 cells was significantly increased following 24 h incubation with the CLA mixture (P < 0.05) and c9,t11-CLA (P < 0.02). In contrast to the MCF-7 cells, 14C-AA uptake into the triglyceride fraction of the SW480 cells was increased while uptake into the phospholipids was reduced following treatment with the CLA mixture (P < 0.02) and c9,t11-CLA (P < 0.05). Distribution of 14C-AA among phospholipid classes was altered by CLA treatments in both cell lines. The c9,t11-CLA isomer decreased (P < 0.05) uptake of 14C-AA into phosphatidylcholine while increasing (P < 0.05) uptake into phosphatidylethanolamine in both cell lines. Both the CLA mixture and the t10,c12-CLA isomer increased (P < 0.01) uptake of 14C-AA into phosphatidylserine in the SW480 cells but had no effect on this phospholipid in the MCF-7 cells. Release of 14C-AA derivatives was not altered by CLA treatments but was increased (P < 0.05) by LA in the SW480 cell line. The CLA mixture of isomers and c9,t11-CLA isomer inhibited 14C-AA conversion to 14C-prostaglandin E2 (PGE2) by 20-30% (P < 0.05) while increasing 14C-PGF2alpha by 17-44% relative to controls in both cell lines. LA significantly (P < 0.05) increased 14C-PGD2 by 13-19% in both cell lines and increased 14C-PGE2 by 20% in the SW480 cell line only. LA significantly (P < 0.05) increased 5-hydroperoxyeicosatetraenoate by 27% in the MCF-7 cell line. Lipid peroxidation, as determined by increased levels of 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha), was observed following treatment with c9,t11-CLA isomer in both cell lines (P < 0.02) and with t10,c12-CLA isomer in the MCF-7 cell line only (P < 0.05). These data indicate that the growth-promoting effects of LA in the SW480 cell line may be associated with enhanced conversion of AA to PGE2 but that the growth-suppressing effects of CLA isomers in both cell lines may be due to changes in AA distribution among cellular lipids and an altered prostaglandin profile.

Topics: Arachidonic Acid; Breast Neoplasms; Carbon Radioisotopes; Cell Survival; Colonic Neoplasms; Dinoprost; Dinoprostone; Humans; Leukotriene B4; Leukotrienes; Linoleic Acid; Prostaglandin D2; Tumor Cells, Cultured

The aim of this work was to study the action of leukotrienes on the growth of human mammary cancer cells MCF-7.. The growth of the cells was measured by incorporation of 3H-thymidine. The action of leukotriene (LT)B4, LTD4, LTC4, LTE4 or arachidonate (AA) was tested in human mammary cancer cells MCF-7 in vitro.. LTB4 or LTD4 but not LTC4 or LTE4 reduced significant incorporation of 3H-thymidine in MCF-7 cells up to 52% or 56% respectively, when administered in concentrations 0.1-1000 pM. Agents in concentrations of 0.01 pM or 10000 pM did not effect 3H-thymidine incorporation. We have shown, that MCF-7 cells synthesise LTB4 when treated with calcium ionophor A23187 (10 microM). Leukotriene-antagonist LY171883 (10 microM) lifts inhibitory effects of LTB4 or LTD4. Arachidonic acid (10 microM) inhibits 3H-thymidine incorporation up to 72%. 5-lipoxygenase inhibitor MK-886 (100 nM) lifts the inhibitory effect of arachidonate.. LTB4 or LTD4 inhibits MCF-7 breast cancer cell growth. LT-receptors mediate the growth-inhibitory effect of LTB4 or LTD4.

Topics: Acetophenones; Arachidonic Acid; Breast Neoplasms; Calcimycin; Carcinoma; Cell Division; Female; Humans; Indoles; Ionophores; Leukotriene Antagonists; Leukotriene B4; Leukotriene D4; Leukotrienes; Lipoxygenase Inhibitors; Osmolar Concentration; Tetrazoles; Thymidine; Tritium; Tumor Cells, Cultured

The aim of this study was to investigate the direct effect of 5-lipoxygenase (5-LO) on the growth of human mammary cancer cells MCF-7 in vitro. Cell growth was measured according to the level of 3H-thymidine incorporation. 5-LO was shown to inhibit 3H-thymidine incorporation. The inhibitory effect was 19, 42 and 78% when administered at concentrations of 0.1, 0.2 or 0.5 U/ml, respectively. Its effect was time- and dose-dependent and was statistically significant at concentrations of 0.2 and 0.5 U/ml. We have also shown that the specific 5-LO inhibitor MK-886 (1 microM) lifts the inhibitory effect of 5-LO (0.2 U/ml). Moreover, when treated with an activator of 5-lipoxygenase calcium ionophore A23187 (10 microM) MCF-7 cells synthesize LTB4. The results of this study are evidence of the role of 5-lipoxygenase in the regulation of human mammary cancer cells growth in vitro.

Topics: Arachidonate 5-Lipoxygenase; Breast Neoplasms; Calcimycin; Cell Division; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Indoles; Leukotriene B4; Lipoxygenase Inhibitors; Thymidine; Tumor Cells, Cultured

We investigated the effects of cyclooxygenase and lipoxygenase inhibitors in the presence of linoleic acid (LA), as well as the direct effects of prostaglandin E (PGE) and leukotriene B (LTB) on a human breast cancer cell line (MDA-MB-231) in vitro. Piroxicam, esculetin, and nordihydroguaiaretic acid (NDGA) suppressed cell growth and thymidine incorporation. However, a low concentration (1 microgram/ml) of indomethacin (INDO) stimulated cell growth and thymidine incorporation, while a high concentration of INDO (30 micrograms/ml) inhibited both. Esculetin and NDGA reduced the secretion of LTB, whereas piroxicam reduced the secretion of PGE. INDO reduced the secretion of PGE, but a low concentration of INDO increased the secretion of LTB. Consequently, cell growth was correlated with the PGE and/or LTB concentrations when the cells were treated with these cyclooxygenase or lipoxygenase inhibitors. On the other hand, exogenous PGE2 partially reversed the inhibition of thymidine incorporation caused by INDO, whereas LTB4 exerted a similar effect in the case of esculetin or NDGA. The reversibility of the piroxicam effect with PGE2 is not convincing. Therefore, it is suggested that the growth of MDA-MB-231 cells in vitro is affected by both the lipoxygenase and cyclooxygenase products, probably the other eicosanoids rather than PGE2 and LTB4.

Topics: Breast Neoplasms; Cell Division; Cyclooxygenase Inhibitors; Dinoprostone; Female; Humans; Leukotriene B4; Linoleic Acid; Linoleic Acids; Lipoxygenase Inhibitors; Tumor Cells, Cultured

The effect of indomethacin (INDO) with or without the addition of linoleic acid (LA) was investigated in a cultured MDA-MB-231 human breast cancer cell line. It was found that INDO without LA suppressed cell growth and thymidine incorporation; however, with the addition of LA, INDO at low concentration promoted these factors, whereas INDO at higher concentrations suppressed them. On the other hand, INDO with or without the addition of LA reduced the secretion of prostaglandin E (PGE). However, INDO at a low concentration (1 microgram/ml) with the addition of LA increased the secretion of leukotriene B (LTB), while INDO without LA had no effect on the secretion of LTB. When the relationship between cell growth and PGE or LTB concentration was investigated, cell growth was associated with the PGE and LTB concentrations when the cells were treated with INDO and LA, whereas it was associated only with the PGE and LTB concentrations when the cells were treated with INDO and LA, whereas it was associated with the PGE concentration when they were treated with INDO alone.

Topics: Breast Neoplasms; Cell Division; DNA, Neoplasm; Female; Humans; Indomethacin; Leukotriene B4; Linoleic Acid; Linoleic Acids; Prostaglandins E; Thymidine; Tumor Cells, Cultured

It has been reported that ubenimex, a biological response modifier, has a direct anti-tumor effect. To clarify the mechanism involved, we examined the effects of ubenimex on the growth and adhesive property of a breast cancer cell line YMB-S. The cells proliferate in a floating manner without aggregation in normal complete medium. Ubenimex induced cell-cell and cell-surface adhesion of the cells accompanied with growth suppression. E-Cadherin localized at cell-cell contact sites of adhered cells, and anti-E-cadherin antibody inhibited the adhesion. Both Western blot analysis and binding assay disclosed that there was no apparent difference between E-cadherin levels of the cells before and after the treatment with ubenimex. These results indicate that ubenimex inhibits the proliferation of YMB-S cells and augments cell-to-cell adhesion through the induction of E-cadherin-mediated adhesion resulting from the functional activation of pre-expressed but inefficient E-cadherin.

Topics: Antibiotics, Antineoplastic; Antibodies; Breast Neoplasms; Cadherins; Carcinoma, Ductal, Breast; Cell Adhesion; Cell Aggregation; Cell Division; Collagen; Culture Media; Drug Combinations; Humans; Immunohistochemistry; Laminin; Leucine; Leukotriene B4; Neoplasm Invasiveness; Proteoglycans; Tumor Cells, Cultured

We investigated the effects of piroxicam, esculetin, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) on a human breast cancer cell line (MDA-MB-231). Both piroxicam and esculetin suppressed cell growth and thymidine incorporation, though esculetin was more active in inhibiting cell growth in the presence of linoleic acid (LA). Esculetin reduced the secretion of LTB independent of LA. Piroxicam reduced the secretion of PGE in the absence of LA but only at higher concentrations in the presence of LA. When the relationship between cell growth and PGE and LTB concentration was evaluated by multivariate regression analysis, cell growth was associated with the PGE and LTB concentration when the cells were treated with esculetin alone or with esculetin and LA. Cell growth was associated only with the PGE concentration when they were treated with piroxicam alone or with piroxicam and LA. Therefore, it appears that the growth of MDA-MB-231 cells in vitro is affected by both lipoxygenase and cyclooxygenase products, though lipoxygenase inhibition is more active than cyclooxygenase inhibition on suppression of cell growth in the presence of LA.

Topics: Breast Neoplasms; Cell Division; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Leukotriene B4; Multivariate Analysis; Piroxicam; Tumor Cells, Cultured; Umbelliferones

Monoclonal antibodies (MAb's) [anti-Leu-1, anti-Leu-2a (T8), anti-Leu-3a (T4), and anti-Leu-4 (T3)] were used to elucidate the type of T-cell mediating leukocyte adherence inhibition (LAI) and the role of T-cell surface glycoproteins in LAI. T8+ (Leu-2a+) and T4+ (Leu-3a+) subtypes were isolated by panning. T8+ (Leu-2a+) cells showed LAI to extracts of autologous cancer, whereas the T4+ (Leu-3a+) subset had no LAI response. Moreover, MAb to the T8+ (Leu-2a+) glycoprotein negated T-cell LAI, but MAb to Leu-1+ or to T4+ (Leu-3a+) did not negate T-cell LAI to autologous cancer extracts. The T3+ (Leu-4+) differentiation also was essential for T-cell LAI to autologous cancer extracts since anti-Leu-4 (T3) negated the response. Since LAI to autologous cancer extracts depends ultimately on leukotriene and other oxidative metabolites of arachidonic acid generated by the T-cell binding tumor antigen, the effect of MAb on LAI induced by leukotriene B4 isomer III. 5(S), 12(R)-dihydroxy-6, 14-cis-8, 10-trans-eicosatetraenoic acid (LTB4) was examined. Authentic LTB4 induced nonadherence of 34% of adherent T-cells, and this effect was not negated by anti-Leu-1, anti-T8 (Leu-2a), or anti-T4 (Leu-3a). However, anti-T3 (Leu-4) abrogated LTB4-induced LAI of pure T-cells without any effect on the basic adherence properties of T-cells. The present findings indicated that LAI to autologous cancer extracts was mediated by T-cells of the T8+ phenotype when they recognize tumor antigen and polymorphic major histocompatibility complex determinants on autologous cancer membranes. Moreover, differentiation glycoproteins T8+ (Leu-2a+) and T3+ (Leu-4+) on the surface of the responding effector T-cells performed distinct biologic functions that enabled the tumor antigen to trigger T-cell LAI.

Topics: Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Breast Neoplasms; Glycoproteins; Humans; Leukocyte Adherence Inhibition Test; Leukotriene B4; Membrane Proteins; T-Lymphocytes

Whereas leukocytes from patients with early cancer usually show leukocyte adherence inhibition (LAI) to the sensitizing cancer extract, leukocytes from patients with advanced cancer seldom do. The chemoattractant-induced LAI response was studied to determine whether the abnormal response by leukocytes from patients with advanced cancer was related to changes in sensitivity to chemoattractants. Authentic chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine, chemotactic fragment of the fifth component of complement, and leukotriene B4 (LTB4) at optimum concentrations induced about 28-31% of adherent leukocytes to become nonadherent, these leukocytes being from either controls or patients with early breast cancer. However, chemoattractants induced no increased nonadherence of adherent leukocytes from patients with advanced breast cancer. In the control tubes, nonadherent cells for patients with advanced cancer were already increased by about 38% and were slightly greater than the chemoattractant-induced increased of nonadherent cells for control subjects or patients with early cancer. When the intracellular cyclic AMP of the cells were raised transiently, the nonadherent cells in the control tubes for patients with advanced cancer decreased by about 38% compared to 8% for control subjects and 13% for patients with early cancer. When nonadherence was returned to control levels, about 46% of adherent cells from patients with advanced cancer became nonadherent to chemoattractants or to the sensitizing cancer extract. Normal leukocytes, preexposed to chemoattractants, had increased nonadherence and did not respond to the same or other chemoattractants, imitating the state of leukocytes from patients with advanced cancer. However, if the cells were washed and intracellular cyclic AMP raised, nonadherent cells returned to normal levels in the control tubes and showed increased nonadherence with a repeat LTB4 exposure. The increased nonadherence of leukocytes from patients with advanced cancer as well as the refractoriness to chemoattractants was highly suggestive of in vivo activation of leukocytes possibly because of exposure to chemoattractant-like factors, generated by leukocyte-tumor antigen interactions.

Topics: Breast Neoplasms; Cell Adhesion; Chemotactic Factors; Chemotaxis, Leukocyte; Female; Humans; Leukocyte Adherence Inhibition Test; Leukocytes; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neoplasm Staging; Neoplasms; Tissue Extracts