title: Cancer cells cue the p53 response of cancer-associated fibroblasts to cisplatin.
abstract: Current understanding of the p53 response is based mainly upon in vitro studies of homogeneous cell populations. However, there is little information on whether the same principles operate within heterogeneous tumor tissues that are comprised of cancer cells and other cell types, including cancer-associated fibroblasts (CAF). Using ex-vivo tissue cultures, we investigated p53 status and responses to cisplatin in tumor cells and CAFs from tissue specimens isolated from 32 lung cancer patients. By comparing cultivated tissue slices with the corresponding tumor tissues fixed immediately after surgery, we found that morphology, proliferation, and p53 staining pattern were preserved during cultivation. Unexpectedly, when CAFs were analyzed, p53 accumulation and induction of p21 was observed only in tumors with constitutively low p53 protein and accumulation upon cisplatin treatment. In contrast, in tumors with no p53 accumulation in cancer cells there was also no p53 accumulation or p21 induction in adjacent CAFs. Furthermore, induction of cisplatin-induced apoptosis in CAFs was selectively observed in tumors characterized by a parallel induction of cancer cell death. Our findings reveal an interdependence of the p53 response in cancer cells and adjacent CAFs within tumor tissues, arguing that cancer cells control the response of their microenvironment to DNA damage.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
authors.forename: Jens O
authors.initials: JO
authors.lastname: Schmid
authors.forename: Meng
authors.initials: M
authors.lastname: Dong
authors.forename: Silke
authors.initials: S
authors.lastname: Haubeiss
authors.forename: Godehard
authors.initials: G
authors.lastname: Friedel
authors.forename: Sabine
authors.initials: S
authors.lastname: Bode
authors.forename: Andreas
authors.initials: A
authors.lastname: Grabner
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mürdter
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Walter E
authors.initials: WE
authors.lastname: Aulitzky
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin