Biological characterization of two xenografts derived from human CUPs (carcinomas of unknown primary).
BACKGROUND
Carcinomas of unknown primary site (CUP) are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs.


METHODS
We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations.


RESULTS
Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1) was lost after 3 passages whereas the other one (Capi3) has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312) and Capi3 (codon 181); the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3.


CONCLUSIONS
Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors.
Lequin
Delphine
D
Université Paris-Sud, CNRS-UMR 8126 and Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France. delphine.lequin@wanadoo.fr
Fizazi
Karim
K
Toujani
Saloua
S
Souquère
Sylvie
S
Mathieu
Marie-Christine
MC
Hainaut
Pierre
P
Bernheim
Alain
A
Praz
Françoise
F
Busson
Pierre
P
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D018895:Microsatellite Repeats / Q000235:genetics; D008854:Microscopy, Electron; D020125:Mutation, Missense / Q000235:genetics; D009368:Neoplasm Transplantation / Q000473:pathology*; D009382:Neoplasms, Unknown Primary / Q000235:genetics* / Q000473:pathology*; D010997:Pleural Neoplasms / Q000556:secondary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000556:secondary; D014183:Transplantation, Heterologous / Q000473:pathology*
D019009:Proto-Oncogene Proteins c-kit