Emerging evidence suggests that mesenchymal stem cells (MSCs) are often recruited to tumor sites but their functional significance in tumor growth and disease progression remains elusive. Herein we report that prostate cancer (PC) cell microenvironment subverts PC patient adipose-derived stem cells (pASCs) to undergo neoplastic transformation. Unlike normal ASCs, the pASCs primed with PC cell conditioned media (CM) formed prostate-like neoplastic lesions in vivo and reproduced aggressive tumors in secondary recipients. The pASC tumors acquired cytogenetic aberrations and mesenchymal-to-epithelial transition (MET) and expressed epithelial, neoplastic, and vasculogenic markers reminiscent of molecular features of PC tumor xenografts. Our mechanistic studies revealed that PC cell-derived exosomes are sufficient to recapitulate formation of prostate tumorigenic mimicry generated by CM-primed pASCs in vivo. In addition to down-regulation of the large tumor suppressor homolog2 (Lats2) and the programmed cell death protein 4 (PDCD4), a neoplastic transformation inhibitor, the tumorigenic reprogramming of pASCs was associated with trafficking by PC cell-derived exosomes of oncogenic factors, including H-ras and K-ras transcripts, oncomiRNAs miR-125b, miR-130b, and miR-155 as well as the Ras superfamily of GTPases Rab1a, Rab1b, and Rab11a. Our findings implicate a new role for PC cell-derived exosomes in clonal expansion of tumors through neoplastic reprogramming of tumor tropic ASCs in cancer patients.
Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/07/06/jimmunol.100064
BackgroundMembrane vesicles released by neoplastic cells into extracellular medium contain potential of carrying arrays of oncogenic molecules including proteins and microRNAs (miRNA). Extracellular (exosome-like) vesicles play a major role in cell-to-cell communication. Thus, the characterization of proteins and miRNAs of exosome-like vesicles is imperative in clarifying intercellular signaling as well as identifying disease markers.MethodsExosome-like vesicles were isolated using gradient centrifugation from MCF-7 and MDA-MB 231 cultures. Proteomic profiling of vesicles using liquid chromatography-mass spectrometry (LC-MS/MS) revealed different protein profiles of exosome-like vesicles derived from MCF-7 cells (MCF-Exo) than those from MDA-MB 231 cells (MDA-Exo).ResultsThe protein database search has identified 88 proteins in MDA-Exo and 59 proteins from MCF-Exo. Analysis showed that among all, 27 proteins were common between the two exosome-like vesicle types. Additionally, MDA-Exo contains a higher amount of matrix-metalloproteinases, which might be linked to the enhanced metastatic property of MDA-MB 231 cells. In addition, microarray analysis identified several oncogenic miRNA between the two types vesicles.ConclusionsIdentification of the oncogenic factors in exosome-like vesicles is important since such vesicles could convey signals to non-malignant cells and could have an implication in tumor progression and metastasis.
The hyaluronan receptor CD44 plays an important role in facilitating invasion and metastasis of a variety of tumors, including breast carcinomas. CD44 functions as a bioactive signaling transmitter. Although a number of studies have implicated CD44 in breast tumor invasion, the evidence is still circumstantial. We have developed a tetracycline-regulated CD44s (standard form) system in the weakly metastatic breast cancer cell MCF7, which exhibits low endogenous expression of CD44 and generated a new cell line, MCF7F-B5. Induction of CD44s alone affected the growth characteristics of MCF7F-B5 cells by increasing their abilities to proliferate, migrate, and invade in vitro. In addition, we have identified and validated cortactin as a novel transcriptional target of hyaluronan/CD44s signaling in underpinning breast tumor invasion. To test these observations in vivo, we developed a doxycycline (DOX)-regulated CD44s breast cancer xenograft model. Induction of CD44s did not affect the growth rate or local invasion of the primary tumor. However, although no mice from the ؉DOX group developed metastasis, 8 of 11 mice from the ؊DOX group developed secondary tumors to the liver only. Interestingly, metastatic breast tumors expressed high levels of CD44. This study provides in vivo evidence for the role of the standard form of CD44 in promoting breast tumor invasion and metastasis to the liver. Breast cancer cells metastasize from the original tumor site through the vasculature to distant organs such as the liver, lungs, brain, and bones. These cells also invade and exfoliate into body cavities, especially the pleural space, where they grow in suspension within effusions.1 Invasion is the defining event for cancer and the recurring step in the metastatic process. Cell invasion depends, in great part, on the ability of invading cells to attach to and then detach from various types of cells and extracellular components. Although moving to secondary sites, tumor cells use a new set of adhesion, migration, and homing proteins. The adhesion molecule CD44 (also known as homing protein, PGP-1, Hermes antigen, and HUTCH-1) is the principal cell surface receptor for hyaluronic acid (HA), although other extracellular matrix (ECM) proteins, including collagen, fibronectin, and osteopontin, can bind CD44.2 Via its interaction with HA, CD44 functions as a bioactive signaling transmitter, leading to diverse effects on cellular adhesion, migration, and invasion-all of which are important processes in cancer progression as well as in hematopoietic development and wound healing. [3][4][5] CD44 is a ubiquitous multistructural and multifunctional cell surface adhesion molecule involved in cell-cell and cell-matrix interactions. It is the most studied alternatively spliced gene in cancer. Of its 20 exons, the first and last five exons are constant, whereas the 10 intermediate exons are subject to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons generates multiple i...
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