Pten Loss and RAS/MAPK Activation Cooperate to Promote EMT and Metastasis Initiated from Prostate Cancer Stem/Progenitor Cells

Abstract

PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, our findings indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective gin preventing the development of metastatic prostate cancers.

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

“…Next, we continued to determine whether miR-19 positively modulates EMT, migration, and invasiveness of cancer cells in vitro via regulation of PTEN. Increasing evidence supports that inactivation or downregulation of the tumor suppressor PTEN can trigger EMT of cancer cells, [60][61][62][63] which then promoted the invasion and metastasis of various cancers including lung cancer. 42,[49][50][51][52][53][54][55][56][57] It has been reported that PTEN negatively regulated the PI3K/ Akt pathway through the dephosphorylation of PI(3,4,5)P3, and ultimately participated in the regulation of cell cycle, proliferation, apoptosis, adhesion, and EMT during cancer progress.…”

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

“…The RAS/MAPK pathway is significantly elevated in both primary and metastatic prostate cancer, and its activation promotes aggressive tumor behavior, but there is no information about its implication in tumor initiation. 36,37 Although CHKB has been shown to be involved in carcinogenesis in different types of solid tumors, to our knowledge, it has not been studied in human prostate cancer. 38 Different metalloproteinases, including MMP13, which has previously been linked to prostate cancer, were also up-regulated in the ODC-overexpressing cells in our study.…”

Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells

“…The profound changes in cytoskeletal architecture that occur during EMT, together with a reduction in intercellular adhesion and an increase in motility, are fundamental to the metastatic process, enabling these cells to break through the basal membrane and migrate over long distances (21). The EMT is considered to be a significant step in the invasive cascade, facilitating the migration of tumor cells from their site of origin and their dissemination to distant tissues (22). EMT is a complex, stepwise phenomenon that is involved in embryonic development, as well as other physiological and pathological conditions, playing a role in enhancing the invasive and metastatic behavior of cancer cells.…”