A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity

A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a dist...

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Published in:Cancer research (Chicago, Ill.) Vol. 78; no. 9; pp. 2318 - 2331
Main Authors: Díaz-Carballo, David, Saka, Sahitya, Klein, Jacqueline, Rennkamp, Tobias, Acikelli, Ali H, Malak, Sascha, Jastrow, Holger, Wennemuth, Gunther, Tempfer, Clemens, Schmitz, Inge, Tannapfel, Andrea, Strumberg, Dirk
Format: Journal Article
Language:English
Published: United States American Association for Cancer Research, Inc 01-05-2018
Subjects:
Apoptosis
Cell fate
Chemotherapy
Ejection
Heterogeneity
Immune system
Immunosuppression
Life cycles
Metastases
Offspring
Ovarian cancer
Ovarian carcinoma
Parturition
Polyploidy
Pregnancy
Proteins
Stem cells
Tumor cells
Tumors
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Summary:The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy-refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers. P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. .
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-17-1861