this issue [15–20]. It is likely that the reporters used to depict the E
and M states in these studies are activated in a wide range of EMT
values rather than strictly at one of the two extremes of the spectrum. Clearly, using only one reporter, such as FSP-1, to quantify
the EMT status is far from sufficient to describe the position of
carcinoma cells on the EMT spectrum. A single- or double knockout does not guarantee that these carcinoma cells have not retained
mesenchymal-like features, even if they do express E-cadherin
[21]. A recent study [22] provides additional support to the importance of intermediate EMT states, with distinct subpopulations of
intermediate EMT-staged carcinoma cells exhibiting either tumor
initiation and expansion or invasive and metastatic properties.
These different populations are localized in distinct microenvironments in primary tumors. Cells with intermediate EMT values are
more prone to invasion and metastasis than their epithelial counterpart, indicative of a role for EMT in the progression of
carcinoma.
However, it remains to be determined precisely when cells
acquire stemness and how stable is the phenotype [23]. One way
to approach this critical issue is to decipher how somatic cells can be
reprogrammed into stem cells. To achieve reprogramming, somatic
cells must be brought into a fully mesenchymal state, during which
a dramatic reorganization of the chromatin renders the cells susceptible to stem cell transcription factors. The acquisition of stemness appears to occur during the MET process, initiated through
the combined actions of EMT inhibitors and MET inducers
[24, 25]. Stemness is likely acquired at an intermediate stage during
reversal to the epithelial state. It remains unclear whether both
normal and carcinoma cells can acquire stem-like properties at
similar or distinct intermediates stages and the stability of these
phenotypes in carcinoma cells. Carcinoma cell plasticity is also
exploited to induce the transdifferentiation of breast carcinoma
cells into adipocytes [26]. Interestingly, the reprogramming of
breast carcinoma cells into adipocytes will prevent their invasion
and metastasis.
The question remains: Are intermediate phenotypes seen during carcinoma progression? There is accumulating evidence for the
existence of intermediate-staged EMT in human primary tumors
and in circulating tumor cells [27–29]. The EMT spectrum seen
among all tumor types also points to intermediate stages in primary
tumors, and this is further reflected in the spectrum of EMT noted
in corresponding carcinoma cell lines [14]. Future studies will
address in depth the mechanisms driving carcinoma cell plasticity
in relation to the microenvironment for the design of better therapeutic strategies.
EMT: An Update
37
and M states in these studies are activated in a wide range of EMT
values rather than strictly at one of the two extremes of the spectrum. Clearly, using only one reporter, such as FSP-1, to quantify
the EMT status is far from sufficient to describe the position of
carcinoma cells on the EMT spectrum. A single- or double knockout does not guarantee that these carcinoma cells have not retained
mesenchymal-like features, even if they do express E-cadherin
[21]. A recent study [22] provides additional support to the importance of intermediate EMT states, with distinct subpopulations of
intermediate EMT-staged carcinoma cells exhibiting either tumor
initiation and expansion or invasive and metastatic properties.
These different populations are localized in distinct microenvironments in primary tumors. Cells with intermediate EMT values are
more prone to invasion and metastasis than their epithelial counterpart, indicative of a role for EMT in the progression of
carcinoma.
However, it remains to be determined precisely when cells
acquire stemness and how stable is the phenotype [23]. One way
to approach this critical issue is to decipher how somatic cells can be
reprogrammed into stem cells. To achieve reprogramming, somatic
cells must be brought into a fully mesenchymal state, during which
a dramatic reorganization of the chromatin renders the cells susceptible to stem cell transcription factors. The acquisition of stemness appears to occur during the MET process, initiated through
the combined actions of EMT inhibitors and MET inducers
[24, 25]. Stemness is likely acquired at an intermediate stage during
reversal to the epithelial state. It remains unclear whether both
normal and carcinoma cells can acquire stem-like properties at
similar or distinct intermediates stages and the stability of these
phenotypes in carcinoma cells. Carcinoma cell plasticity is also
exploited to induce the transdifferentiation of breast carcinoma
cells into adipocytes [26]. Interestingly, the reprogramming of
breast carcinoma cells into adipocytes will prevent their invasion
and metastasis.
The question remains: Are intermediate phenotypes seen during carcinoma progression? There is accumulating evidence for the
existence of intermediate-staged EMT in human primary tumors
and in circulating tumor cells [27–29]. The EMT spectrum seen
among all tumor types also points to intermediate stages in primary
tumors, and this is further reflected in the spectrum of EMT noted
in corresponding carcinoma cell lines [14]. Future studies will
address in depth the mechanisms driving carcinoma cell plasticity
in relation to the microenvironment for the design of better therapeutic strategies.
EMT: An Update
37