lewis-y-antigen and Prostatic-Neoplasms

This study was conducted to gain a better understanding of the underlying cellular events involved in the development of prostatic intraepithelial neoplasia (PIN) and to clarify the relationship of PIN to invasive prostatic adenocarcinoma (PCa).. This article reviews previous studies from our laboratory and others of biomarker expression in PIN and PCa.. The development of PIN is characterized by increased expression of several biomarkers which may influence the proliferative potential of the dysplastic cells. Increased expression of the growth factor receptors P185erbB-2, p180erbB-3, as well as the product of the c-met proto-oncogene is frequently detected in the dysplastic luminal cells as well as malignant cells of the prostate. Likewise, the expression of the nm-23H1 gene product is strongly expressed in dysplastic and malignant cells. Increased proliferative potential of the dysplastic cells is directly reflected by increased expression of PCNA. In contrast to the enhanced expression of the biomarkers associated with proliferation, decreased expression of prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and Leu 7 by dysplastic luminal cells is indicative of an impairment of the process of cellular differentiation. Aberrant glycosylation as well as the inappropriate expression of glycosylated tumor antigens is demonstrated by enhanced binding of the lectin Ulex europaeus and increased expression of tumor-associated glycoprotein 72 (TAG-72) and the Lewis Y antigen in dysplastic and malignant cells. Finally, enhanced expression of proteolytic enzymes such as cathepsin D and the 72-kD form of collagenase IV by dysplastic cells may represent an integral event in the development of invasive PCa.. The studies described in this review clearly demonstrate phenotype similarities of PIN to invasive PCa and furthermore support the concept that PIN represents a preinvasive lesion.

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers; Gene Expression Regulation, Neoplastic; Glycoproteins; Glycosylation; Humans; Lewis Blood Group Antigens; Male; Oncogene Proteins; Phenotype; Prostate-Specific Antigen; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Proto-Oncogene Mas; Receptors, Growth Factor

The immunotoxin BR96 sFv-PE40 is an effective antitumor agent against human breast and lung carcinoma xenografts in rodents. This study was designed to (a) determine the frequency with which canine carcinoma cells express Lewis(y) (Le(y)) antigen, thereby identifying canine carcinoma types suitable for the clinical evaluation of BR96 sFv-PE40, and (b) determine the safety and efficacy of BR96 sFv-PE40 in a canine model of spontaneously occurring cancers for investigation of targeted therapy.. Carcinoma tissue samples were obtained from client-owned dogs presented for medical care. The tissues were assessed for Le(y) antigen expression using immunohistochemical methods. Dogs with tumors expressing Le(y) antigen were offered enrollment in a clinical trial to receive twice-weekly infusions of 4 to 12 mg/m(2) BR96 sFv-PE40. Clinical toxicity and response data were assessed at each treatment.. Twenty-two of 61 carcinomas evaluated were positive for Le(y) expression, including mammary, prostate, lung, and rectal carcinomas, and 12 dogs were enrolled in the clinical trial. The primary side effect was transient emesis. Partial responses or disease stabilization were noted in dogs with inflammatory mammary, bronchogenic, rectal, and tonsillar carcinoma. At least nine of the dogs developed antibodies to the immunotoxin after two to five infusions.. Although development of anti-BR96 sFv-PE40 antibodies limited the long-term effectiveness of this immunotoxin in dogs, rapid clinical responses in several aggressive canine carcinomas suggest the immunotoxin has utility for treatment of certain naturally occurring tumors and that its clinical evaluation for treatment of similar human carcinomas is warranted.

Topics: Animals; Antibodies, Monoclonal; Dogs; Female; Immunotherapy; Immunotoxins; Lewis Blood Group Antigens; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Neoplasm Invasiveness; Prostatic Neoplasms; Recombinant Fusion Proteins; Rectal Neoplasms

We have previously reported on a carbohydrate-based vaccine program for immunotherapy in cancer patients. One such vaccine, based on the globo H antigen conjugated to the protein keyhole limpet hemocyanin (KLH), has been in clinical evaluation. Although this and other carbohydrate vaccines have been shown to induce antibody responses, there are currently no quantitative data on the antibody levels achieved in immunized patients by these or other anti-cancer vaccines. We report herein an efficient route to complex synthetic oligosaccharides attached to an affinity matrix for identifying and isolating antibodies elicited against such a carbohydrate-based vaccine in humans. Pre- and postvaccination profiles from serum samples of patients immunized with globo H-KLH were compared. All anti-globo H antibody activity was efficiently separated from other serum constituents. The isolated antibodies were readily quantified, and their specificities were analyzed. Since no comparable data were available on antibodies resulting from the vaccination of other cancer patients, we compared the observed levels with those quoted in studies with bacterial polysaccharide vaccines that had been quantified. Remarkably, cancer patients immunized with globo H-KLH produce anti-globo H antibody levels often exceeding those formed by immunization with bacterial polysaccharides. In addition, substantial quantities of both IgG and IgM antibodies were elicited, clearly indicating a class switch to IgG. Taken together, these analyses serve to clarify several aspects of the immune response to the vaccine and give several new insights to the carbohydrate-based vaccination strategy. Furthermore, antibodies so isolated could well have applications in clinical therapy.

Topics: Antibodies; Antibody Specificity; Cancer Vaccines; Carbohydrate Sequence; Chromatography, Affinity; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin G; Lewis Blood Group Antigens; Male; Molecular Sequence Data; Prostatic Neoplasms; Vaccines, Conjugate; Vaccines, Synthetic

Alteration of cell surface carbohydrate antigens during malignant transformation is a well-known phenomenon observed in various tumors. In prostatic carcinoma, nearly total deletion of normally occurring ABO and type I-based Lewis antigens, Le(a) and Leb, has been observed in several studies. We studied expression of the closely related type II antigens Le(x), Le(y), and sialyl-Lewis(x) (SLe(x)) using monoclonal antibodies. Thirty formalin-fixed specimens obtained from radical prostatectomy, containing prostatic carcinoma as well as benign tissue, were evaluated by immunohistochemistry. In both cancer and benign tissue, Le(x) expression was minimal or absent. In benign tissue, Le(y) was expressed in ducts and in the basal layer of glandular epithelium. In tumor tissue, Le(y) expression was greatly increased and extensive staining was observed in 26 of 30 cases. The SLe(x) expression in benign tissue was observed only in larger ducts, never in glandular secretory epithelial cells. In carcinoma, rare cells positive for SLe(x) were present in 8 of 30 cases, and stronger expression with focal to patchy distribution was observed in 14 of 30 cases. The results suggest an alteration in glycosyl transferase activity in prostatic carcinoma, with preserved or increased activity of enzymes responsible for the synthesis of the type II core sequence. This sequence is further glycosylated and expressed as the difucosylated compound Le(y) or the monofucosyl, monosialyl compound SLe(x). For prostate, Le(y) and SLe(x) are the only blood group-related antigens known to be minimal or absent in benign secretory epithelial cells that are more highly expressed in malignant tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomarkers, Tumor; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Male; Oligosaccharides; Prostatic Neoplasms; Sialyl Lewis X Antigen

We used the monoclonal antibody BR96 to determine the expression of the Lewis Y antigen in benign and malignant prostatic tissues. Strong immuno-staining was detected within the basal cells of benign glands in 29 of 30 specimens examined. In contrast, weak immuno-staining of the secretory (luminal) epithelium was detected in only 10 of these same 30 specimens. Moderate to strong immuno-staining of luminal cells, however, was observed in prostatic intraepithelial neoplasia in 15 of 17 specimens. Immuno-staining was detected within the malignant cells in all 49 specimens of primary prostatic adenocarcinoma examined. We used a semiquantitative technique to compare the extent of immuno-staining among well (combined Gleason score less than 6), moderately (combined Gleason score 6 to 7) and poorly (combined Gleason score more than 7) differentiated tumors as well as metastatic lesions. Poorly differentiated tumors demonstrated the greatest extent of immuno-staining compared to moderately and well differentiated adenocarcinoma. Strong immuno-staining was also detected within the malignant cells in 7 metastatic (5 nodal lesions and 2 bone marrow biopsies) tumors. The extent of immuno-staining in the metastatic lesions was similar to that observed in the poorly differentiated primary tumors. In summary, the Lewis Y antigen, as detected by BR96, is widely expressed within prostatic adenocarcinomas. Furthermore, the poorly differentiated as well as metastatic lesions frequently demonstrated the highest expression of the Lewis Y antigen.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Neoplasm; Humans; Immunoenzyme Techniques; Lewis Blood Group Antigens; Male; Prostate; Prostatic Neoplasms