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.
Highlights
One of the major molecular players in cellular stress responses is the p53 tumor suppressor protein
The range of Ki67 scores obtained from cultivated tissue samples significantly correlated to that of the corresponding tissues fixed immediately after surgery (Fig. 1A, right) and was comparable to Ki67 scores described in non–small cell lung carcinoma (NSCLC) patient studies [19]
Using this ex vivo model, we were able to show a close correlation of the stress responses of cancer cells and the nonmalignant cancer-associated fibroblasts (CAF) in intact lung tumor tissues: both accumulation of the major stress regulator p53 and induction of cell death were found to be coordinately regulated in the cancer and stromal compartments
Summary
One of the major molecular players in cellular stress responses is the p53 tumor suppressor protein. P53 is rapidly degraded and, not present at detectable levels in the cell. Upon various types of cellular stresses, p53 gets stabilized and rapidly accumulates within the nucleus [1,2,3]. The tight regulation of the p53 system is impaired in most if not all cancers [4]. More than 50% of all tumors carry TP53 mutations [5, 6]. In many of the remaining cancers p53 is thought to be inactivated, for example, through loss of upstream regulators such as ARF [7] or overexpression of p53 inhibitors such as Mdm or MdmX [8]
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