Department of Pathology and Oncology, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Respir Res. 2020 Jul 16;21(1):187. doi: 10.1186/s12931-020-01449-2.
Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis.
We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype.
In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression.
These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.
间皮瘤在组织学上分为三个亚组：上皮样、肉瘤样和双相型。上皮样或肉瘤样型分别由多边形或梭形细胞形态定义。双相型由这两种成分组成。目前尚不清楚间皮瘤的组织学分化是如何调节的。ERC/间皮素在大多数上皮样型中表达，但不在间皮瘤的肉瘤样型中表达。因此，其表达与组织学亚型密切相关。我们假设 ERC/间皮素的表达影响间皮瘤的组织学分化，并对此假设进行了检验。
我们通过在间皮瘤细胞中过表达或敲低 ERC/间皮素，研究其对细胞形态、生长动力学或体外迁移/侵袭活性的影响。然后，我们将 ERC/间皮素过表达和对照细胞移植到小鼠的腹腔内。我们检查了 ERC/间皮素过表达对小鼠存活和肿瘤表型的影响。
体外细胞培养中 ERC/间皮素表达的调控并不影响细胞形态或增殖，但过表达 ERC/间皮素增强了间皮瘤细胞的黏附性和迁移/侵袭活性。与对照组相比，腹腔内移植 ERC/间皮素过表达间皮瘤细胞的小鼠存活率明显降低。然而，对肿瘤的组织学评价并未显示两组之间有任何形态学差异，我们的假设未得到验证。出乎意料的是，体外形态上均为单相和梭形的两组间皮瘤细胞在移植瘤中分化为具有多边形和梭形成分的双相型，而与 ERC/间皮素的表达无关。
这些结果表明，间皮瘤上皮样和肉瘤样类型之间的组织学转变可能是可逆的，并且不是由 ERC/间皮素调节的，而是由其他未知机制调节的。
