Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus.
We hypothesized that the development of the most resistant cells during metastasis is favored by anti-apoptotic proteins, leading to the acquisition of an adaptive phenotype crucial to drug resistance at the metastatic foci. In order to test it, we induced metastasis in nude mice, injecting orthotopicaly 435/Bcl-x(L) or 435/Neo cells, transfected previously with the luciferase gene to use it as a tumor marker, and treated them with a therapeutic dose of docetaxel. We monitored metastasis in mice by calculating tumor cell equivalents (TCEs) present in tissues. Between docetaxel-treated and non-treated 435/Bcl-x(L).luc mice significant differences in the metastatic burden of lymph nodes (P = 0.02) and viscera (P = 0.02) were observed. However, treatment did not significantly decrease metastatic burden in bones (P = 0.19). Additionally, we analyzed the clonality of metastasis from lung, bone and lymph node by genomic DNA fingerprinting. Bcl-x(L) enhanced cell genetic instability in terms of gain and loss fractions (GF = 0.18 and LF = -0.21) when compared with the control 435/Neo (GF = 0.15 and LF = -0.14). Thus, genetic instability might be a molecular mechanism favored by Bcl-x(L) evolved in the selection process of breast cancer progression, which results in different genetic changes among metastases from lung, bone or lymph node, favoring organ-selective chemoresistance.
Gu
Bin
B
Centre d'Oncologia Molecular, Institut de Recerca Oncológica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona, Spain.
España
Laura
L
Méndez
Olga
O
Torregrosa
Angels
A
Sierra
Angels
A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D016172:DNA Fingerprinting; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009928:Organ Specificity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D051020:bcl-X Protein; D000077143:Docetaxel; D008156:Luciferases