Shiga-like toxin-1 receptor on human breast cancer, lymphoma, and myeloma and absence from CD34(+) hematopoietic stem cells: implications for ex vivo tumor purging and autologous stem cell transplantation.
The ribosome-inactivating protein, Shiga-like toxin-1 (SLT-1), targets cells that express the glycolipid globotriaosylceramide (CD77) on their surface. CD77 and/or SLT-1 binding was detected by flow cytometry and immunocytochemistry on lymphoma and breast cancer cells recovered from biopsies of primary human cancers as well as on B cells or plasma cells present in blood/bone marrow samples of multiple myeloma patients. Breast cancer cell lines also expressed receptors for the toxin and were sensitive to SLT-1. Treatment of primary B lymphoma, B-cell chronic lymphocytic leukemia, and myeloma B or plasma cells with SLT-1-depleted malignant B cells by 3- to 28-fold, as measured by flow cytometry. Depletion of myeloma plasma cells was confirmed using a cellular limiting dilution assay followed by reverse transcriptase-polymerase chain reaction analysis of clonotypic IgH transcripts, which showed a greater than 3 log reduction in clonotypic myeloma cells after SLT-1 treatment. Receptors for the toxin were not detected on human CD34(+) hematopoietic progenitor cells (HPC). HPC were pretreated with a concentration of SLT-1 known to purge primary malignant B cells and cultured for 6 days. The number of HPC was comparable in toxin-treated and untreated cultures. HPC were functionally intact as well. Colony-forming units (CFU) were present at an identical frequency in untreated and SLT-1 pretreated cultures, confirming that CFU escape SLT-1 toxicity. The results suggest the ex vivo use of SLT-1 in purging SLT-1 receptor-expressing malignant cells from autologous stem cell grafts of breast cancer, lymphoma, and myeloma patients.
LaCasse
E C
EC
Department of Medical Biophysics, University of Toronto and the Ontario Cancer Institute, Toronto, Ontario, Canada.
Bray
M R
MR
Patterson
B
B
Lim
W M
WM
Perampalam
S
S
Radvanyi
L G
LG
Keating
A
A
Stewart
A K
AK
Buckstein
R
R
Sandhu
J S
JS
Miller
N
N
Banerjee
D
D
Singh
D
D
Belch
A R
AR
Pilarski
L M
LM
Gariépy
J
J
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000737:chemistry / Q000187:drug effects; D001427:Bacterial Toxins / Q000494:pharmacology*; D015415:Biomarkers; D014408:Biomarkers, Tumor; D001773:Blood Cells / Q000737:chemistry; D001854:Bone Marrow Cells / Q000737:chemistry; D016465:Bone Marrow Purging / Q000379:methods*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy; D002277:Carcinoma / Q000737:chemistry / Q000473:pathology / Q000628:therapy; D002469:Cell Separation / Q000379:methods*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry; D005803:Genes, Immunoglobulin; D006017:Glycolipids / Q000032:analysis*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000737:chemistry*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000737:chemistry* / Q000473:pathology / Q000628:therapy; D008224:Lymphoma, Follicular / Q000737:chemistry / Q000473:pathology / Q000628:therapy; D008297:Male; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000032:analysis*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects; D009928:Organ Specificity; D010950:Plasma Cells / Q000737:chemistry / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022622:Shiga Toxin 1; D014182:Transplantation, Autologous; D014281:Trihexosylceramides / Q000032:analysis*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D015415:Biomarkers; D014408:Biomarkers, Tumor; D006017:Glycolipids; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; C068556:Shiga-like toxin receptor; D014281:Trihexosylceramides; C018549:globotriaosylceramide