Dudley AC, Shih SC, Cliffe AR, Hida K, Klagsbrun M.. Attenuated p53 activation in tumour-associated stromal cells accompanies decreased sensitivity to etoposide and vincristine. Br J Cancer 99: 118-125

Vascular Biology Program, Department of Surgery, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
British Journal of Cancer (Impact Factor: 4.84). 08/2008; 99(1):118-25. DOI: 10.1038/sj.bjc.6604465
Source: PubMed


Alterations in the tumour suppressor p53 have been reported in tumour-associated stromal cells; however, the consequence of these alterations has not been elucidated. We investigated p53 status and responses to p53-activating drugs using tumour-associated stromal cells from A375 melanoma and PC3 prostate carcinoma xenografts, and a spontaneous prostate tumour model (TRAMP). p53 accumulation after treatment with different p53-activating drugs was diminished in tumour-associated stromal cells compared to normal stromal cells. Tumour-associated stromal cells were also less sensitive to p53-activating drugs - this effect could be reproduced in normal stromal cells by p53 knockdown. Unlike normal stromal cells, tumour stromal cells failed to arrest in G(2) after etoposide treatment, failed to upregulate p53-inducible genes, and failed to undergo apoptosis after treatment with vincristine. The lower levels of p53 in tumour stromal cells accompanied abnormal karyotypes and multiple centrosomes. Impaired p53 function in tumour stroma might be related to genomic instability and could enable stromal cell survival in the destabilising tumour microenvironment.

Download full-text


Available from: K. Hida, Apr 26, 2014
  • Source
    • "CAFs are large, spindle-shaped mesenchymal cells that share characteristics with smooth muscle cells and fibroblasts [6]. They constitute a significant component of the stroma and represent the cells responsible for the change of extracellular matrix composition into one with increased amounts of collagens (desmoplastic response) [3]. Currently, no precise definition of CAFs exists because of the different cellular origin and markers expressed: CAFs are likely to derive from resident fibroblasts and marrow-derived mesenchymal precursor cells, whereas their generation through epithelial-mesenchymal transition (EMT) of tumor cells is more controversial [6,9,10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.
    Full-text · Article · May 2014 · Cancer Cell International
  • Source
    • "Almost all high-grade ovarian serous carcinoma cells acquire TP53 mutations [10], and multiple reports have indicated that altered p53 expression in cancer fibroblasts, perhaps not mutational events, act to promote stromal cell involvement in stimulating tumorigenesis [36]. Indeed, evidence suggests that human prostate and breast cancer fibroblasts express a nonmutated, but functionally deficient, form of p53 [37] [38], expanding on mouse and cell-based studies pointing to a selective mechanism exerted by tumorigenic epithelial cells for synergistic growth and development with p53-attenuated fibroblasts [13,39–42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer has long been considered a disease that mimics an "unhealed wound," with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α), IL-6, IL-1β, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.
    Full-text · Article · Apr 2013 · Neoplasia (New York, N.Y.)
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The p53 tumor suppressor serves as a crucial barrier against cancer development. In tumor cells and their progenitors, p53 suppresses cancer in a cell-autonomous manner. However, p53 also possesses non-cell-autonomous activities. For example, p53 of stromal fibroblasts can modulate the spectrum of proteins secreted by these cells, rendering their microenvironment less supportive of the survival and spread of adjacent tumor cells. We now report that epithelial tumor cells can suppress p53 induction in neighboring fibroblasts, an effect reproducible by tumor cell-conditioned medium. The ability to suppress fibroblast p53 activation is acquired by epithelial cells in the course of neoplastic transformation. Specifically, stable transduction of immortalized epithelial cells by mutant H-Ras and p53-specific short inhibitory RNA endows them with the ability to quench fibroblast p53 induction. Importantly, human cancer-associated fibroblasts are more susceptible to this suppression than normal fibroblasts. These findings underscore a mechanism whereby epithelial cancer cells may overcome the non-cell-autonomous tumor suppressor function of p53 in stromal fibroblasts.
    Full-text · Article · Feb 2009 · Oncogene
Show more