Tumor-derived microvesicles: The metastasomes Reza Ghasemi a,b , Antonino Grassadonia a , Nicola Tinari a , Enza Piccolo a , Clara Natoli a , Federica Tomao c Stefano Iacobelli a,⇑ a Department of Biomedical Sciences, University of ‘‘G. D’Annunzio’’ of Chieti-Pescara, Italy b Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran c Department of Gynecology & Obstetrics, University of Rome ‘‘Sapienza’’, Rome, Italy article info Article history: Received 1 June 2012 Accepted 18 October 2012 abstract Metastasis is the leading cause of cancer death, yet it is mechanistically considered a very inefficient pro- cess suggesting the presence of some sort of (e.g. systemic) routes for fuelling the process. The pre-met- astatic niche formation is described as one such metastasis promoting route. Now, the emerging potentials of tumor-derived microvesicles (TDMVs), not only in formulating the pre-metastatic niche, but also conferring neoplastic phenotypes onto normal cells, has integrated new concepts into the field. Here, we note as an ancillary proposition that, exerting functional disturbances in other sites, TDMVs (we have termed them metastasomes) may aid foundation of the secondary lesions via two seemingly inter- related models: (i) tumor-organ-training (TOTr), training a proper niche for the growth of the dissemi- nated tumor cells; (ii) tumor-organ-targeting (TOTa), contribution to the propagation of the transformed phenotype via direct or indirect (TOTr-mediated disturbed stroma) transformation and/or heightened growth/survival states of the normal resident cells in the secondary organs. Respecting the high content of the RNA molecules (particularly microRNAs) identified in the secretory MVs, they may play crucial parts in such ‘‘malignant trait’’ spreading system. That is, the interactions between tumor tis- sue-specific RNA signatures, being transferred via metastasomes, and the cell-type/tissue-specific RNA stockrooms in other areas may settle a unique outcome in each organ. Thus, serving as tumor-organ matchmakers, the RNA molecules may also play substantial roles in the seeding and tropism of the process. Ó 2012 Elsevier Ltd. All rights reserved. Introduction The term ‘‘metastasis’’ was initially created in 1829 by Jean Claude Recamier and is defined as ‘‘the transfer of disease from one organ or part to another not directly connected to it’’ [1]. Malignant disease can be dated back to Egyptians (1500 BC) and latter to the Greek physicians in the time of Hippocrates (5th cen- tury BC) who detected fatal secondary lesions in breast cancer pa- tients. Although such lesions were primarily considered as ‘‘independent tumors’’ arisen from the spread of ‘‘toxic humors’’, with the discovery of cell as the basic unit of organisms, this theory was abandoned and the secondary lesions were supposed to arise from the migration and seeding of tumor cells from primary sites into the others (reviewed in Ref. [2]). Since then, despite the sev- eral (e.g. seed-soil) models [3], the mechanism of tumor metastasis has remained enigmatic. In fact, based on the current models, a proposed metastasis founder cell must go through the sequential series of inefficient steps (separation from the primary tumor, intravasation, survival in the circulation, extravasation, and suc- cessful colonization in the secondary organs) to found a clinically detectable metastasis [3]. Two questions can be raised here: first, how can metastasis become the main cause of cancer death if it is a very inefficient process? Second, how could the disseminated tumor cells (DTCs) stay dormant even for decades in the eccentric and tumor-suppressive microenvironments of the ectopic regions [4,5] to give then rise to tumor recurrence? Together these conun- drums, with the notion that the metastasis founder cell is yet un- known [6], may force a major rethinking of the process. Perhaps, we are missing some parts of the landscape that might be due to our reductionistic views. In this situation, putting all the possibili- ties together to unravel the matter of metastasis becomes impor- tant, as it will provide a base for definition of more effective treatment options and therapeutic strategies. It is increasingly becoming evident that the tumor ‘‘cell’’ migra- tion from primary site into distant organs is a simplistic view or only a part of the whole panorama of the cancer ‘‘disease’’ dissem- ination process. Recently, the interplay between primary tumor and secondary organs via circulation has emerged as an essential component of tumor metastasis [6,7]. While cancer cells can 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.10.011 ⇑ Corresponding author. Address: Department of Biomedical Sciences, University of ‘‘G. D’Annunzio’’, Via dei Vestini 31, 66100 Chieti, Italy. Tel.: +39 0871 355 6732; fax: +39 0871 355 6707. E-mail address: iacobell@unich.it (S. Iacobelli). Medical Hypotheses 80 (2013) 75–82 Contents lists available at SciVerse ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy