A transgenic mouse model for early prostate metastasis to lymph nodes, "Beyond the Abstract," by Irwin H. Gelman, PhD

BERKELEY, CA (UroToday.com) - A major unresolved issue in prostate cancer (CaP) is whether metastasis occurs early or late relative to disease in the primary site. This understanding is critical to many types of new analyses, such as quantifying circulating tumor cells (CTC) or whole exome sequencing, meant to better monitor CaP progression or predict which patients might fail androgen-ablation therapy. Simply put, if metastatic colonization occurs early, then monitoring CTC number or searching for metastasis genomic signatures in mid- to late-stage disease have diminished value over existing markers such as PSA doubling.

Leading up our current Cancer Research paper,[1] the literature had only a few studies that addressed the issue of early vs late metastasis in CaP, as well as the issue of which primary-site CaP cells serve as the progenitors of metastases. Haffner et al.[2] addressed the issue of cell-of-origin in general terms, showing, somewhat surprisingly, that one patient’s lethal metastatic clone was far more genetically related to a minor, low-grade primary-site CaP focus than to his majority high-grade CaP lesion. Further, support for the notion of early metastatic dissemination includes data that over 50% of human prostate cancer cases with minimal primary site disease show evidence of PSA-positivity in the bone marrow[3] or disseminated tumor cells in local lymph nodes.[4, 5]

Our study focused on developing a transgenic model to study the early events in CaP metastasis. Specifically, mice were produced that had a prostate-specific deficiency of the Rb gene, encoding a known suppressor of CaP progression,[6] plus a deficiency in the SSeCKS/Akap12 gene, encoding a suppressor of CaP metastasis.[7] Mice deficient in only Rb or SSeCKS/Akap12 exhibited prostatic hyperplasia, whereas mice with the combined deficiency suffered from high-grade prostatic intraepithelial neoplasia (HG-PIN) by 5 months of age. Most interestingly, these mice also exhibited, by 7 months of age, dissemination of CaP cells to local draining lymph nodes (LN). Neither the PIN nor the LN lesions progressed to aggressive adenocarcinomas, even after 2 years, suggesting that the LN metastasis resulted from an early colonization event. In regards to the cell-of-origin issue, we noted that the LN metastases expressed markers of both basal and luminal prostate epithelial cells, such as cytokeratin 14 and p63 (basal), and cytokeratin 8 and androgen receptor (luminal); interestingly, these lesions lacked the basal markers, cytokeratin 5. Further analysis of the HG-PIN lesions from these mice identified multiple foci of proliferating basal cells, in which there was an increased frequency of cytokeratin 5 loss and androgen receptor gain, strongly suggesting that these are the progenitors of the LN metastases. If correct, this would suggest that the LN lesion cells in our model represent HG-PIN cells transitioning from the basal to luminal phenotype, agreeing with recent assessments that CaP malignancy can arise from basal cells that differentiate to express luminal markers.[8]

The last major significance of our study is that our data suggest that SSeCKS/Akap12 suppresses the metastatic progression of CaP, in part by inhibiting chemotaxis and invasiveness driven by the Src tyrosine kinase pathway. This likely relates to the ability of the SSeCKS protein to scaffold active Src away from plasma membrane domains rich in adhesion- and growth factor-receptors to so-called lipid rafts membrane domains, without affecting Src kinase activity.[9] The result is that in the presence of SSeCKS, Src is disengaged from protein partners that activate MAP Kinase and STAT signaling pathways controlling the expression of invasion proteins, such as metalloproteinases, and controlling actin cytoskeleton structures that govern oncogenic cell motility, such as chemotaxis. Given that the expression of SSeCKS/AKAP12 is downregulated in clinical cases of CaP LN metastases compared to primary-site CaP, and that downregulation correlates with significantly earlier occurrence of CaP metastasis, the loss of SSeCKS would likely translate on a molecular level with the activation of Src-driven pro-metastatic pathways. These data strongly suggest that the early targeting Src pathways with known clinical inhibitors, such as dasatinib,[10] would decrease the incidence of subsequent metastatic disease.

References:

  1. Ko H-K, Akakura S, Peresie J, Goodrich DW, Foster BA, Gelman IH. A transgenic model for early prostate metastasis to lymph nodes. Cancer Res 2014;74:945-53.
  2. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest 2013;123:4918-22.
  3. Wood DP, Jr., Banks ER, Humphreys S, McRoberts JW, Rangnekar VM. Identification of bone marrow micrometastases in patients with prostate cancer. Cancer 1994;74:2533-40.
  4. Holcomb IN, Grove DI, Kinnunen M, Friedman CL, Gallaher IS, Morgan TM, et al. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res 2008;68:5599-608.
  5. Holcomb IN, Young JM, Coleman IM, Salari K, Grove DI, Hsu L, et al. Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. Cancer Res 2009;69:7793-802.
  6. Lee JT, Lehmann BD, Terrian DM, Chappell WH, Stivala F, Libra M, et al. Targeting prostate cancer based on signal transduction and cell cycle pathways. Cell Cycle 2008;7:1745-62.
  7. Gelman IH. Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev 2012;31:493-500.
  8. Xin L. Cells of origin for cancer: an updated view from prostate cancer. Oncogene 2013;32:3655-63.
  9. Su B, Gao L, Meng F, Guo LW, Rothschild J, Gelman IH. Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by SSeCKS/AKAP12. Oncogene 2013;32:2016-26.
  10. Lara PN, Jr., Evans CP. Dasatinib and docetaxel in advanced prostate cancer. Lancet Oncol 2013;10-2045.

Written by:
Irwin H. Gelman, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

John and Santa Palisano Chair of Cancer Genetics
Professor of Oncology
Director, Cell & Molecular Biology Academic Program
Leader, Comprehensive Cancer Center Genetics Program
Roswell Park Cancer Institute
Buffalo, NY USA

A transgenic mouse model for early prostate metastasis to lymph nodes - Abstract

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