Signet Ring Cells

Another cell type that is associated with cancer is a structure called a "signet ring cell." Two characteristics of signet cells have been of particular interest to cancer researchers. Representation of signet ring cells is so substantial in some cancers that they have been called signet ring carcinoma, a search term that calls up more than 5000 journal articles in Pub Med. Signet ring cells have also been associated with apoptosis (programmed cell death) as attested to by more than 1200 entries brought up with the "signet ring cell and apoptosis." As was true for "optically clear nuclei," signet ring cells are observed during studies of Ishikawa endometrial epithelia differentiation. The formation of these structures follows upon the appearance of chromatin with vacuoles.

Signet ring cells are the second significant structure formed when Ishikawa endometrial epithelial cells differentiate into domes. In our system, the "cells" are actually mitonucleons formed according to the description provided for figs. 2 and 3 on the home page.

Fig. 4 Dense heterochromatic structures, resulting from nuclear aggregation in the first few hours of differentiation are observed to contain vacuoles. A second much larger vacuole forms outside of the chromatin during the predome stage of differentiation. The vacuole causes the apical membrane to unfurl up into the medium above the monolayer. Initially, the chromatin aggregate pressured against the apical membrane rises up with the protrusion, surrounded by small structures believed to be centrioles. This picture is of a predome, neither fixed nor stained, taken with a blue filter that emphasized some of the features of a structure otherwise difficult to observe with the microscope. The force that could accomplish this structural change is the generation of a very lare gas vacuole.

Fig. 5 Fixed and stained protrusions in a predome illustrate the extent to which aggregated chromatin is compressed during this stage of differentiation. Structures like this have been observed both in normal, but more frequently in cancerous tissue. The highly compressed chromatin, polyploid as demonstrated by its mode of formation, is sometimes called pyknotic, and is often assumed to signal the advent of programmed cell death, apoptosis. Apoptosis is not the result of pyknosis in this system, although, as the next figure demonstrates pyknotic nuclear aggregates do undergo changes.

Fig. 6 Pycnotic nuclear structure together with the mitonucleon structure begin to fall apart in the next stage of differentiation. One of the mitonucleons is leaking material back into the cytosol, and the nuclear structure has faded. Another way to describe what is happening at this stage in the differentiation process is that chromatin material is taking up much less hematoxylin because its structure is changing. In the literature, such a process has been called karyolysis. Three terms frequently appear together. These are karyopyknosis or pyknosis, karyolysis, and karyorrhexis.

Origins of signet ring cells based on observations of differentiating endometrial epithelial cancer cells in vitro.

Signet ring cells , is the name used to identify cells in which the nucleus (polyploid in Ishikawa differentiation) is displaced from the center of a "cell" by a giant vacuole. The resulting structure in epithelial endometrial cell culture is not a type of epithelial cell but a stage in differentiation of monolayer epithelial cells into domes and, under appropriate conditions, into gland-like structures. Could it be the case that "signet ring carcinoma" so-named because of the presence of numerous signet ring cells is actually a carcinoma in which some proliferation is occurring by the process of amitosis as described in this website.

An outstanding difference between our observations and those made in vivo is the assumption that gases are not involved in vacuole formation. What is found in vacuoles following processing of cancer tissue is mucin. Of course there is no expectation that processed tissue would retain gases suggesting that mucin might be all that is left following tissue processing.

In vitro (Fleming, 2018) the vacuole responsible for unfurling apical membranes and pressuring chromatin against the mitonucleon is generated in a matter of a couple hours. It appears that gas is built up within vesicular variant of internal membranes in the giant spheroidal fused mitochondria of the mitonucleon. The identities of gases in the giant vacuole are not known, although CO2, NO, and even H2 have been suggested.

Fleming H. 2018. Mitochondrial/Nuclear Superstructures Drive Morphological Changes in Endometrial Epithelia by Pressure Exerted when Gas vacuoles Form and Coalesce Within Superstructures. Advances in Bioscience and Biotechnology Vol.9 No.5,DOI:10.4236/abb.2018.95016

Giant vacuole causes apical membranes to unfurl up into the medium above the mitonucleon as it compresses aggregated chromatin into a structure resembling pyknotic nuclei. Ultimately the pressure of the giant vacuole causes the breakdown of the mitonucleon with the resulting processes of karyolysis and karyorrhexis.

Selected recent reviews elicited with the search term signet ring cell carcinoma. Many more are available.

Grilliot MA, Goldblum JR, Liu X. 2012 Signet ring cell melanoma of the gastroesophagealjunction: A case report and literature review. Arch Pathol Lab Med. 136(3):324-8.Kollas, A., Zarkavelis, G., Goussia, A., Kafantari, A., Batistatou, A., Evangelou, Z., Sintou, E., … Pavlidis, N. (2016). Testicular Signet-Ring Cell Metastasis from a Carcinoma of Unknown Primary Site: A Case Report and Literature Review. Case reports in oncological medicine, 2016, 7010173.Park P.Y. · Goldin T.· Chang J. · Markman M. · Kundranda M.N. 2015 Signet-Ring Cell Carcinoma of the Colon: A Case Report and Review of the Literature Case Rep Oncol 8:466-471Pernot, S., Voron, T., Perkins, G., Lagorce-Pages, C., Berger, A., & Taieb, J. (2015). Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World journal of gastroenterology, 21(40), 11428-38.Radojkovic M. Ilic D. Ilic I. Primary signet ring cell carcinoma of the pancreas with a good response to chemotherapy: case report and literature review. Tumori. 2017 Nov 15;103(Suppl. 1):e50-e52. doi: 10.5301/tj.5000671.

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