In the last decades cancer prevailed as one of the most common human diseases with lung cancer toping the ranking. Different theories have tried to explain the emergence, development and progression of human tumors, although none have yet fully succeeded on its task. Typically, cancer is characterized by progressive series of alterations that disrupt cell and tissue homeostasis. Though, whereas many of those alterations can be induced by gene-specific mutations, faulty signals from the microenvironment can also act as inducers of tumor development and progression (1). Recent findings revealed that despite tumors are comprised of heterogeneous cell populations, only a small fraction of cells have the ability to self-renew and to produce phenotypically diverse populations. This fraction of cells named cancer stem cells (CSCs) has been identified in many cancers and blamed for resistance to conventional cancer therapies and tumor relapse (2). The link between CSCs and metastases has also been suggested by several studies despite only a few of them have directly tested the metastatic capability of putative CSCs in vivo (3). The attained results showed that even though in vitro the CSCs phenotype alone may exhibit invasive properties, in vivo this phenotype may not be enough to determine or predict metastases formation. In fact, albeit two distinct CD133+ pancreatic CSCs sub-populations with tumorigenic potential can be isolated, just the subpopulation concomitantly positive for CD133 and CXCR4 caused liver metastases (4). Moreover, growing evidence supports the idea that chemo and/or radiotherapy spares or even enriches the CSCs population within the original tumor by killing the bulk of the tumor cells (5). Answer to these questions is essential and will have a tremendous impact in clinical practice. If tumorigenic cells really represent minor populations within the tumors, improved anti-cancer therapies should be addressed to specifically kill these CSCs rather than the population of non-tumorigenic cancer cells. The methodic search for CSCs specific markers, aiming their isolation and characterization, is becoming one of the main focuses of cancer biology. Initially, it was proposed that CSCs originate from mutations in tissue-specific stem cells (SCs) that induce dysregulated self-renewal properties and selectively drive tumor growth (6). Yet, it has recently been demonstrated that tumor cells are able to undergo epithelial to mesenchymal transition (EMT), acquiring CSC-like features. In fact, induction of EMT in immortalized human mammary epithelial cells led to the expression of CSC markers, increased self-renewal capacity, and enhanced tumor formation (7). This process explains the presence of EMT characteristics of CSCs, i.e., the loss of E-cadherin and the increased expression of fibronectin, vimentin, N-cadherin and of the mesenchymal transcription factors Snail, Twist and Slug (7). But the ultimate origins of CSCs remain controversial. Whether CSCs arise from pre-existing tissue SC, restricted progenitor cells or from dedifferentiation of terminally differentiated cells likely depends on the context. Nonetheless, each of these scenarios is consistent with the idea that distinct populations of cells with SC properties are essential for the development and perpetuation of various human cancers. Hexavalent chromium [Cr(VI)] is a recognized environmental and occupational human lung carcinogen. Through inhalation, Cr(VI) nanoparticles deposit at lung bifurcations and slowly dissolve, chronically exposing airway cells to the carcinogen. Lung cancer is the common long-term consequence of these exposures (8). Aiming to understand the molecular mechanisms underlying Cr(VI)-induced LC, we successfully established the first in vitro system depicting the multi-step process of Cr(VI)–induced malignant transformation (9). We also implemented several other cell lines with increasing malignant potential by serial rounds of xenotransplantations in athymic mice (10). Our most recent studies on the these cellular systems revealed the presence of sub-populations of CSCs only in the more malignant cell lines, suggesting that they were originated by dedifferentiation of epithelial cells that eventually underwent EMT. Considering our results, we now want to characterize the isolated CSCs populations present in our different cellular systems, evaluate their abundance and highlight their molecular signature using specific molecular markers. Additional functional tests will help us to fully characterize these lung-specific CSCs populations. Altogether, the obtained data will improve the knowledge on the pathways involved on the different stages of Cr(VI)-induced lung carcinogenesis: onset, progression and metastases formation; and will represent an improvement in the understanding of cancer biology.

• Project/scholarship ID

  128214

• Reference

  PTDC/BBB-BQB/2450/2012

• FundRef URI

  http://www.fct.pt/apoios/projectos/consulta/vglobal_projecto.phtml.en?idProjecto=128214&idElemConcurso=7451

• Funder

  FCT - Fundação para a Ciência e a Tecnologia, I.P.

• Funder's country

  Portugal

• Funding program

  5876-PPCDTI

• Funding amount

  132,248.00 €

• Start date

  2013-05-01

• End date

  2015-09-30