Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases - PubMed (original) (raw)
Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases
Yvonne Chao et al. Cancer Microenviron. 2012 Apr.
Abstract
Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) may occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence supportive of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained paired primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. The metastases exhibited increased expression of membranous E-cadherin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. However, the re-emergence of the epithelial phenotype was only partial or incomplete. Expression of epithelial markers connexins 26 and/or 43 was also increased on the majority of metastases, particularly those to the brain. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged. We also examined prostate carcinoma metastases of varied sizes and found that while E-cadherin expression was increased compared to the primary lesion, the expression inversely correlated with size of the metastasis. This not only suggests that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases, but also provides a basis for the failure to discern epithelial phenotypes in clinically examined macrometastases. In summary, we report increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that readily allows for a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis.
Figures
Fig. 1
Breast cancer metastases exhibit increased localization of adherens junctions components to the membrane. a Quantification of membrane-bound E-cadherin in breast cancer primary tumors and metastases. Representative images of a primary tumor exhibiting cytoplasmic or absent E-cadherin and the paired lung metastasis with membranous E-cadherin expression. *p < 0.05 for all cases and in lung and brain metastases subsets. b Quantification of membranous β-catenin in primary and metastatic tumors. Images from a case that exhibited increased membranous β-catenin staining in a metastasis to the lung. Organ sites of metastases are color-coded: lung (blue), red (liver), and brain (green). Size bar in the photomicrographs is 25 microns
Fig. 2
Expression of gap junctional proteins is increased in breast cancer metastases to the brain. Quantification of membranous Cx26 (a) and Cx43 (b) staining in primary and metastatic breast cancer tumors. Shown are representative images of connexin staining in primary tumors and brain metastases. Organ sites of metastases are color-coded: lung (blue), red (liver), and brain (green). Size bar in the photomicrographs is 25 microns. *p < 0.05 for brain subsets of Cx26 and Cx43
Fig. 3
Mesenchymal markers persist in metastases, suggesting only a partial MErT. Quantification of immunostaining for mesenchymal markers FSP1 (a) and vimentin (b). Images of FSP1 and vimentin staining in primary tumors and metastases. Organ sites of metastases are color-coded: lung (blue), red (liver), and brain (green). Size bar in the photomicrographs is 25 microns
Fig. 4
E-cadherin expression in prostate cancer metastases is inversely correlated with size of metastasis. a Quantification and representative images of prostate cancer primary and metastatic tumors immunostained for E-cadherin. *p < 0.05 Images of three random fields were quantified with ImageJ. b Images of metastatic tumors stained for E-cadherin as categorized by size: small (less than 50 μm in diameter), medium (between 50 μm and 100 μm) and large (bigger than 100 μm). c Quantification of E-cadherin expression in different sized prostate cancer metastases. *p < 0.05. Size bar in the photomicrographs is 25 microns
Fig. 5
Model of reversible phenotypic transitions during metastasis. EMT and loss of E-cadherin enables dissemination, followed by E-cadherin re-expression and a partial MErT that facilitates metastatic colonization at a secondary site. MErT is reversible, and with tumor growth may undergo an additional EMT
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