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Origin and interpretation of cancer transcriptome profiling: the essential role of the stroma in determining prognosis and drug resistance.

Goossens N, Hoshida Y, Aguirre-Ghiso JA - EMBO Mol Med (2015)

View Article: PubMed Central - PubMed

Affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland.

ABSTRACT

Mesenchymal gene expression in tumors has been implicated in cancer recurrence, metastasis, and poor prognosis of patients. The source of these mesenchymal signals has been mostly attributed to the epithelial-to-mesenchymal transition-like phenotype of epithelial tumor cells. However, recent evidence from colorectal and other cancer transcriptome studies clearly shows that the mesenchymal gene expression likely originates from stromal cells in and around the tumor and that this microenvironment specifically confers tumor aggressiveness. These findings highlight the need to move away from tumor-centric interpretations and to better establish the complementary role of the stromal microenvironment in fueling aggressive traits of cancer cells. This observation also suggests that future attempts at transcriptome profiling of whole tumor tissue must take into account the origin of mesenchymal gene expression profiles to better guide development of diagnostic and therapeutic strategies for cancer.

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Origin of mesenchymal gene expression associated with poor prognosis in cancerTop left: Traditional paradigm, indicating the bulk of epithelial tumor cells (yellow and blue) that acquire a mesenchymal phenotype (e.g. EMT-like features) as the source of mesenchymal gene expression (bottom left). These features are undoubtedly associated with poor prognosis (bottom right). Top right: New paradigm, attributing the source of mesenchymal gene expression to stromal cells (orange) in the tumor nodule (gray). The EMT-like tumor lesions on the left certainly contain stromal cells as well, further complicating the identification of the source of the EMT traits even in more “mesenchymal” epithelial tumors. (Cell cartoons from www.servier.com.)
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fig01: Origin of mesenchymal gene expression associated with poor prognosis in cancerTop left: Traditional paradigm, indicating the bulk of epithelial tumor cells (yellow and blue) that acquire a mesenchymal phenotype (e.g. EMT-like features) as the source of mesenchymal gene expression (bottom left). These features are undoubtedly associated with poor prognosis (bottom right). Top right: New paradigm, attributing the source of mesenchymal gene expression to stromal cells (orange) in the tumor nodule (gray). The EMT-like tumor lesions on the left certainly contain stromal cells as well, further complicating the identification of the source of the EMT traits even in more “mesenchymal” epithelial tumors. (Cell cartoons from www.servier.com.)

Mentions: Recent follow-up studies of the CRC EMT-like transcriptome subclass unexpectedly uncovered that the source of mesenchymal gene expression is not the bulk of epithelial tumor cells, but stromal cells such as the cancer-associated fibroblasts within the tumor nodule (Calon et al, 2015; Isella et al, 2015). This finding was verified in patient-derived organoid and xenograft models, and transforming growth factor (TGF)-β signaling was identified as a key factor in the genesis of the poor-prognosis mesenchymal gene signature. These studies underscore that the transcriptome profile of a whole tumor nodule consists of mixed signals of molecular deregulation originating from cells of different types and origin in the nodule, and challenge our interpretation of the EMT program in the cancer cells (Fig1). To establish that the source of poor-prognosis-associated mesenchymal gene expression is a subpopulation of cells of mesenchymal lineage, and not epithelial tumor cells with EMT-like features such as CSCs, despite appearing self-evident, is a fundamental conceptual distinction. In some cases, tumor cells may be the source of the mesenchymal gene expression via trans-differentiation of CSCs into stromal cells as has been documented in glioblastoma stem-like cells (Wang et al, 2010), but the larger proportion of stromal cells recruited from the surrounding tissues may still significantly contribute to these signals. In addition, in a murine model of inflammation-induced gastric cancer, a significant proportion of intratumoral fibroblasts might derive from bone marrow mesenchymal stem cells (Quante et al, 2011).


Origin and interpretation of cancer transcriptome profiling: the essential role of the stroma in determining prognosis and drug resistance.

Goossens N, Hoshida Y, Aguirre-Ghiso JA - EMBO Mol Med (2015)

Origin of mesenchymal gene expression associated with poor prognosis in cancerTop left: Traditional paradigm, indicating the bulk of epithelial tumor cells (yellow and blue) that acquire a mesenchymal phenotype (e.g. EMT-like features) as the source of mesenchymal gene expression (bottom left). These features are undoubtedly associated with poor prognosis (bottom right). Top right: New paradigm, attributing the source of mesenchymal gene expression to stromal cells (orange) in the tumor nodule (gray). The EMT-like tumor lesions on the left certainly contain stromal cells as well, further complicating the identification of the source of the EMT traits even in more “mesenchymal” epithelial tumors. (Cell cartoons from www.servier.com.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644372&req=5

fig01: Origin of mesenchymal gene expression associated with poor prognosis in cancerTop left: Traditional paradigm, indicating the bulk of epithelial tumor cells (yellow and blue) that acquire a mesenchymal phenotype (e.g. EMT-like features) as the source of mesenchymal gene expression (bottom left). These features are undoubtedly associated with poor prognosis (bottom right). Top right: New paradigm, attributing the source of mesenchymal gene expression to stromal cells (orange) in the tumor nodule (gray). The EMT-like tumor lesions on the left certainly contain stromal cells as well, further complicating the identification of the source of the EMT traits even in more “mesenchymal” epithelial tumors. (Cell cartoons from www.servier.com.)
Mentions: Recent follow-up studies of the CRC EMT-like transcriptome subclass unexpectedly uncovered that the source of mesenchymal gene expression is not the bulk of epithelial tumor cells, but stromal cells such as the cancer-associated fibroblasts within the tumor nodule (Calon et al, 2015; Isella et al, 2015). This finding was verified in patient-derived organoid and xenograft models, and transforming growth factor (TGF)-β signaling was identified as a key factor in the genesis of the poor-prognosis mesenchymal gene signature. These studies underscore that the transcriptome profile of a whole tumor nodule consists of mixed signals of molecular deregulation originating from cells of different types and origin in the nodule, and challenge our interpretation of the EMT program in the cancer cells (Fig1). To establish that the source of poor-prognosis-associated mesenchymal gene expression is a subpopulation of cells of mesenchymal lineage, and not epithelial tumor cells with EMT-like features such as CSCs, despite appearing self-evident, is a fundamental conceptual distinction. In some cases, tumor cells may be the source of the mesenchymal gene expression via trans-differentiation of CSCs into stromal cells as has been documented in glioblastoma stem-like cells (Wang et al, 2010), but the larger proportion of stromal cells recruited from the surrounding tissues may still significantly contribute to these signals. In addition, in a murine model of inflammation-induced gastric cancer, a significant proportion of intratumoral fibroblasts might derive from bone marrow mesenchymal stem cells (Quante et al, 2011).

View Article: PubMed Central - PubMed

Affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland.

ABSTRACT

Mesenchymal gene expression in tumors has been implicated in cancer recurrence, metastasis, and poor prognosis of patients. The source of these mesenchymal signals has been mostly attributed to the epithelial-to-mesenchymal transition-like phenotype of epithelial tumor cells. However, recent evidence from colorectal and other cancer transcriptome studies clearly shows that the mesenchymal gene expression likely originates from stromal cells in and around the tumor and that this microenvironment specifically confers tumor aggressiveness. These findings highlight the need to move away from tumor-centric interpretations and to better establish the complementary role of the stromal microenvironment in fueling aggressive traits of cancer cells. This observation also suggests that future attempts at transcriptome profiling of whole tumor tissue must take into account the origin of mesenchymal gene expression profiles to better guide development of diagnostic and therapeutic strategies for cancer.

Show MeSH
Related in: MedlinePlus