Mutant p53 Together with TGFβ Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer

Clin Cancer Res. 2017 Mar 15;23(6):1607-1620. doi: 10.1158/1078-0432.CCR-15-1615. Epub 2016 Sep 16.

Abstract

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored.Experimental Design:KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases.Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases, suggesting that the ability to colonize is, in part, developed within the primary site, a phenomenon we refer to as the "Cinderella effect."Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically. Clin Cancer Res; 23(6); 1607-20. ©2016 AACR.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / pathology
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transforming Growth Factor beta / genetics
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • transcription factor PTF1
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)