title: Prostate Cancer Heterogeneous High-Metastatic Multi-Organ-Colonizing Chemo-Resistant Variants Selected by Serial Metastatic Passage in Nude Mice Are Highly Enriched for Multinucleate Giant Cells.
abstract: In order to further understand the role of tumor heterogeneity in metastasis and chemo-resistance, high metastatic PC-3 human prostate cancer variants were selected by injecting parental PC-3 cells, expressing green fluorescent protein (GFP) in the footpad of nude mice, which then metastasize to inguinal lymph nodes. The PC-3-GFP cells which metastasized to the inguinal lymph nodes were collected and were re-injected to the footpad. After 6 such cycles, the PC-3-GFP cells collected from inguinal lymph nodes (PC-3-GFP-LN) were again injected to the footpad. PC-3-GFP-LN showed 100% metastasis to major lymph nodes (popliteal, inguinal, axillary, and cervical), and 100% metastasis to bone and lung. The percent of giant cell variants was enriched in PC-3-GFP-LN-6 compared to parental cells and increased with each cycle of selection, which in turn had increased metastasis. PC-3-GFP-LN-6 cells were resistant to 5-fluorouracil, doxorubicin and cisplatinum, compared to parental PC-3. However, PC-3-GFP-LN-6 was sensitive to the traditional Chinese medicine (TCM) herbal mixture LQ, similar to the parental cells. These results suggest that PC-3 tumors are heterogenous and that subpopulations of highly metastatic, drug-resistant cells can be step-wise selected using a mouse model of tumor progression.
authors.affiliation: AntiCancer Inc., San Diego, CA, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Traditional Chinese Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, PR China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Wu
authors.affiliation: AntiCancer Inc., San Diego, CA, United States of America.|Department of Surgery, University of California San Diego, San Diego, CA, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use / Q000633:toxicity; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity; D017930:Genes, Reporter; D015726:Giant Cells / Q000166:cytology / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008516:Medicine, Chinese Traditional; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil