Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques
01 Mar 1965-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 121, Iss: 3, pp 439-462
TL;DR: It was shown that the tumor-specific antibodies were not directed against bacterial contaminants or against the unusually high concentrations of fibrin found in many neoplastic tissues.
Abstract: Two methods were used to demonstrate the presence of tumor-specific antigens in adenocarcinomata of the human colon: (a) rabbits were immunized with extracts of pooled colonic carcinomata, and the antitumor antisera thus produced were absorbed with a pooled extract of normal human colon and with human blood components; (b) newborn rabbits were made immunologically tolerant to normal colonic tissue at birth, and were then immunized with pooled tumor material in adult life. Normal and tumor tissues were obtained from the same human donors in order to avoid misinterpretation of results due to individual-specific antigenic differences. The antisera prepared by both methods were tested against normal and tumor antigens by the techniques of agar gel diffusion, immunoelectrophoresis, hemagglutination, PCA, and immunofluorescence. Distinct antibody activity directed against at least two qualitatively tumor-specific antigens, or antigenic determinants, was detected in the antisera prepared by both methods and at least two additional tumor antigens were detected exclusively in antisera prepared by the tolerance technique. Whether these additional antigens were qualitatively different from normal tissue antigens, or merely present in tumor tissue in higher concentrations than in normal tissue has not as yet been determined. Furthermore, it was shown that the tumor-specific antibodies were not directed against bacterial contaminants or against the unusually high concentrations of fibrin found in many neoplastic tissues. It was concluded from these results that the pooled tumor extracts contained tumor-specific antigens not present in normal colonic tissue. Identical tumor-specific antigens were also demonstrated in a number of individual colonic carcinomata obtained from different human donors.
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TL;DR: It was concluded that the carcinoembryonic antigens represent cellular constituents which are repressed during the course of differentiation of the normal digestive system epithelium and reappear in the corresponding malignant cells by a process of derepressive-dedifferentiation.
Abstract: A wide variety of human adult and fetal tissues were studied by immune-diffusion techniques in agar gel to determine whether they contained the tumor-specific antigen(s) previously found in coionic cancers. In the adult tissues it was demonstrated that identical antigens were present in all tested specimens of malignant tumors of the entodermally derived epithelium of the gastrointestinal tract and pancreas, but were absent from all other tested adult tissues. The common antigenic constituents, therefore, represent system-specific cancer antigens of the human digestive system. System-specific cancer antigens have not previously been demonstrated in humans. Experiments with fetal tissues demonstrated that identical antigens were also present in fetal gut, liver, and pancreas between 2 and 6 months of gestation. These components were named "carcinoembryonic" antigens of the human digestive system. On the basis of the present findings and the recent work regarding control of the expression of genetic potentialities in various types of cells, it was concluded that the carcinoembryonic antigens represent cellular constituents which are repressed during the course of differentiation of the normal digestive system epithelium and reappear in the corresponding malignant cells by a process of derepressive-dedifferentiation.
1,796 citations
Cites background or methods from "Demonstration of tumor-specific ant..."
...--Both types of reactions were performed in agar gel plates prepared as previously described (1)....
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...The procedure followed was identical to that previously described (1)....
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...Preparation of the Human Colonic Tumor Tissue Extract (T1)--The pooled colonic tumor tissue extract was prepared according to the method previously described (1)....
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...Interaction of T1 with tl-abs was known to give rise to a reproducible pattern consisting of a single tumor-specific precipitin band (1)....
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...In a previous s tudy reported from this labora tory (1), a t least two common,...
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TL;DR: This chapter considers only those lectins that have been purified to homogeneity, and studied with regard to their biophysical, biochemical, and carbohydrate-binding specificity.
Abstract: Publisher Summary Lectins play an important role in the development of immunology. Lectins also find application in serological laboratories for typing blood and determining secretor status, separating leucocytes from erythrocytes, and agglutinating cells from blood in the preparation of plasma. They serve as reagents for the detection, isolation, and characterization of carbohydrate-containing macromolecules, including blood-group antigens. In their interaction with saccharides, lectins serve as models for carbohydrate-specific antibodies, with the important advantage to purify lectins in gram quantities. Lectins are classified according to their carbohydrate-binding specificity that includes D-mannose(D-glucose)-binding lectins and 2-acetamido-2-deoxy-D-glucose-binding lectins. The chapter considers only those lectins that have been purified to homogeneity, and studied with regard to their biophysical, biochemical, and carbohydrate-binding specificity. The chapter also describes the cell-binding and biological properties of lectins. The chapter concludes with the description of several glycopeptide structures showing the carbohydrate-binding loci with which various lectins interact.
1,540 citations
TL;DR: The most significant recent advances in the application of monoclonal antibodies (mAbs) to oncology have been the introduction and approval of bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody, and of cetuximab (Erbitux) as discussed by the authors.
Abstract: The most significant recent advances in the application of monoclonal antibodies (mAbs) to oncology have been the introduction and approval of bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody, and of cetuximab (Erbitux), an anti-epidermal growth factor antibody. In combination with standard chemotherapy regimens, bevacizumab significantly prolongs the survival of patients with metastatic cancers of the colorectum, breast and lung. Cetuximab, used alone or with salvage chemotherapy, produces clinically meaningful anti-tumor responses in patients with chemotherapy-refractory cancers of the colon and rectum. In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer. These exciting recent results provide optimism for the development of mAbs that bind novel targets, exploit novel mechanisms of action or possess improved tumor targeting. Progress in the clinical use of radioimmunoconjugates remains hindered by complexity of administration, toxicity concerns and insufficiently selective tumor targeting.
1,173 citations
Journal Article•
TL;DR: The anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer.
826 citations
TL;DR: Overcoming Limitations in Nanoparticle Drug Delivery: Triggered, Intravascular Release to Improve Drug Penetration into Tumors and Design Considerations for Tumour-Targeted Nanoparticles.
Abstract: 1.1. Cancer and Early Detection
Cancer is the second most common cause of death in the United States, trailing only heart disease in incidence. Despite significant worldwide investment in research, cancer remains responsible for 1 in 4 deaths in developed countries.1 Globally, over 14 million cancer diagnoses were reported in 2012, a figure expected to increase to over 22 million cases per annum in the next two decades.2 Estimated to kill over 1/2 million U.S. citizens, and with over 1.6 million new cases predicted to be diagnosed this year,3 cancer continues to present a major, yet unmet challenge to healthcare both globally and in the United States.
Cancer emerges from our own tissues, complicating both detection and treatment methods due to the similarities between the diseased tissue and healthy tissue.4,5 Despite this fact, the mortality rate from cancer is often greatly reduced by early detection of the disease. For example, non-small-cell lung cancer is responsible for the most cancer related deaths worldwide, with patients in the advanced stages of the disease having only 5–15% and <2% 5-year survival rates for stage III and IV patients, respectively.6 In contrast, patients who start therapy in the early stages of the disease (stage I) have markedly improved survival rates, with an 80% overall 5-year survival rate.6 Consequently, early diagnosis is essential to improving cancer patient prognosis.
At present, clinical detection of cancer primarily relies on imaging techniques or the morphological analysis of cells that are suspected to be diseased (cytology) or tissues (histopathology). Imaging techniques applied to cancer detection, including X-ray, mammography, computed tomography (CT), magnetic resonance imaging (MRI), endoscopy, and ultrasound, have low sensitivity and are limited in their ability to differentiate between benign and malignant lesions.7,8 While cytology, such as testing for cervical cancer via a Pap smear or occult blood detection, may be used to distinguish between healthy and diseased cells or tissues, it is not effective at detecting cancer at early stages. Similarly, histopathology, which generally relies on taking a biopsy of a suspected tumor, is typically used to probe the malignancy of tissues that are identified through alternative imaging techniques, such as CT or MRI, and may not be used alone to detect cancer in its early stages. As such, the development of assays and methods for early detection of cancer, before the disease becomes symptomatic, presents a major challenge.
Recent research within the field of nanotechnology has focused on addressing the limitations of the currently available methods for cancer diagnosis. Certain nanoparticle probes possess several unique properties that are advantageous for use in the detection of cancer at the early stages. In this review, we will discuss the advances in the development of nanoparticle-based methods for the detection of cancer by fluorescence spectroscopy. We will divide this topic into three categories: techniques that are designed for (1) the detection of extracellular cancer biomarkers, (2) the detection of cancer cells, and (3) the detection of cancerous tissues in vivo. We will discuss these strategies within the context of the nanoparticle probe used as well as the recognition moieties applied in each approach. Ultimately, the translation of these methods from the laboratory to the clinic may enable earlier detection of cancer and could extend patient survival through the ability to administer therapeutic treatment in the early stages of the disease.
While this review provides a comprehensive overview of the nanoparticle probes that are used to detect cancer in vitro and in vivo through fluorescence, there are several other relevant reviews that may be of interest to our readers, who may refer to the references for more generalized reviews of nanomaterials used for diagnostics and therapy,9–12 or more detailed insight into the specific types of nanoparticle probes (i.e., quantum dots,13 gold nanoparticles,14,15 upconversion nanoparticles,16 polymer dots,17,18 silica nanoparticles,19 polymeric nanoparticles, 20 etc.) for cancer diagnosis.
808 citations
References
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TL;DR: In this article, the problem of how to make tissue homografts immunologically acceptable to hosts which would normally react against them has been studied in the context of early foetal life inoculation.
Abstract: The experiments to be described in this article provide a solution—at present only a ‘laboratory’ solution—of the problem of how to make tissue homografts immunologically acceptable to hosts which would normally react against them. The principle underlying the experiments may be expressed in the following terms: that mammals and birds never develop, or develop to only a limited degree, the power to react immunologically against foreign homologous tissue cells to which they have been exposed sufficiently early in foetal life. If, for example, a foetal mouse of one inbred strain (say, CBA) is inoculated in utero with a suspension of living cells from an adult mouse of another strain (say, A), then, when it grows up, the CBA mouse will be found to be partly or completely tolerant of skin grafts transplanted from any mouse belonging to the strain of the original donor. This phenomenon is the exact inverse of ‘actively acquired immunity’, and we therefore propose to describe it as ‘actively acquired tolerance’. The distinction between the two phenomena may be made evident in the following way. If a normal adult CBA mouse is inoculated with living cells or grafted with skin from an A-line donor, the grafted tissue is destroyed within twelve days (see below). The effect of this first presentation of foreign tissue in adult life is to confer ‘immunity’, that is, to increase the host’s resistance to grafts which may be transplanted on some later occasion from the same donor or from some other member of the donor’s strain. But if the first presentation of foreign cells takes place in foetal life, it has just the opposite effect: resistance to a graft transplanted on some later occasion, so far from being heightened, is abolished or at least reduced. Over some period of its early life, therefore, the pattern of the host’s response to foreign tissue cells is turned completely upside down. In mice, it will be seen, this inversion takes place in the neighbourhood of birth, for there is a certain ‘null’ period thereabouts when the inoculation of foreign tissue confers neither tolerance nor heightened resistance—when, in fact, a ‘test graft’ transplanted in adult life to ascertain the host’s degree of immunity is found to survive for the same length of time as if the host had received no treatment at all.
2,867 citations
TL;DR: Small amounts of antibody were occasionally visible in cells in the lymphoid follicles of the spleen and lymph nodes, so that a minor contribution by lymphocytes to antibody synthesis cannot be excluded.
Abstract: A method for the specific histochemical demonstration of antibody in cells and parts of cells is described. It consists of carrying out a two stage immunological reaction on frozen sections of tissues: (a) allowing reaction between antibody in the tissue and dilute antigen applied in vitro, and (b) the detection of those areas where this antigen has been specifically absorbed by means of a precipitin reaction carried out with fluorescein-labelled antibody. Examination under the fluorescence microscope reveals the yellow-green fluorescence of fluorescein over those areas where a precipitate has formed. A study of the hyperimmune rabbit on the first few days after the last of a series of intravenous antigen injections reveals that antibody against human gamma-globulin or ovalbumin is present in groups of plasma cells in the red pulp of the spleen, the medullary areas of lymph nodes, the submucosa of the ileum, and the portal connective tissue of the liver. Because of extensive non-specific reactions, the bone marrow could not be examined. Small amounts of antibody were occasionally visible in cells in the lymphoid follicles of the spleen and lymph nodes, so that a minor contribution by lymphocytes to antibody synthesis cannot be excluded.
1,531 citations
"Demonstration of tumor-specific ant..." refers methods in this paper
...The indirect or "sandwich technique" of Coons (30) was carried out using sheep anti-rabbit "y-globulin antiserum t conjugated to fluorescein (27)....
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TL;DR: Treatment of sheep erythrocytes with suitable concentrations of tannic acid render them capable of adsorbing certain protein molecules from solution in saline, and small amounts of the antigens can be detected through their power to inhibit hemagglutination of the treated cells.
Abstract: Treatment of sheep erythrocytes with suitable concentrations of tannic acid render them capable of adsorbing certain protein molecules from solution in saline. Red cells which have adsorbed proteins in this way are agglutinated after washing by the homologous antiprotein sera, even by high dilutions. Through hemagglutination sera can be titrated for antibodies against antigens adsorbed on the cells exposed to tannic acid. Furthermore, small amounts of the antigens can be detected through their power to inhibit hemagglutination of the treated cells.
1,209 citations
TL;DR: The experiments reported here constitute a further improvement of this procedure which obviates time-consuming dialysis and permits fluorescent labelling of protein solutions, removal of hydrolysed or unreacted dye and change of buffer as well as pH in less than 30 min.
Abstract: A NOVEL method for the fluorescent labelling of proteins has been described recently which involved treatment of a protein solution with an active labelling dye dispersed, on diatomaceous earth or other inert materials1. This modification afforded a considerable saving in time and minimized protein denaturation as compared with earlier techniques. The experiments reported here constitute a further improvement of this procedure which obviates time-consuming dialysis and permits fluorescent labelling of protein solutions, removal of hydrolysed or unreacted dye and change of buffer as well as pH in less than 30 min.
348 citations
"Demonstration of tumor-specific ant..." refers methods in this paper
...In the immunofinorescent studies, antiserum-ffuorescein conjugation was performed as described by Rinderknecht (27) and non-specific staining material removed by the technique of Goldstein et al....
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...The indirect or "sandwich technique" of Coons (30) was carried out using sheep anti-rabbit "y-globulin antiserum t conjugated to fluorescein (27)....
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324 citations