Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

Abstract

Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg-equivalent to one trillion cells-is not compatible with life. While localized disease is curable through surgical removal or radiation, once cancer has spread, it is largely incurable. The inability to cure metastatic cancer lies, at least in part, to the fact that cancer is resistant to all known compounds and anticancer drugs. The source of this resistance remains undefined. In fact, the vast majority of metastatic cancers are resistant to all currently available anticancer therapies, including chemotherapy, hormone therapy, immunotherapy, and systemic radiation. Thus, despite decades-even centuries-of research, metastatic cancer remains lethal and incurable. We present historical and contemporary evidence that the key actuators of this process-of tumorigenesis, metastasis, and therapy resistance-are polyploid giant cancer cells.

Keywords: cancer ecology; keystone species; metastasis; polyploid giant cancer cells; stemness; therapeutic resistance.

Figure 1. Historical evidence of polyploid giant cancer cells.

(A) Illustration (Plate II, Fig 2) from Ueber den feinern Bau und die Formen der krankhaften Geschwülste (translated: On the Finer Structure and Form of Morbid Tumors) by Johannes Müller, 1838; Caption translates “Cell spheres with germ cells and the nuclei of the germ cells…of Carcinoma reticulare.” (Public domain, CC BY-SA 4.0) (B) Illustration (Fig 142) from Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebenlehre (translated: Cellular pathology as based upon Physiological and Pathological Histology) by Rudolph Virchow, 1858 (translated by Frank Chance); Caption: “Various, polymorphous cancer-cells…two with multiplication of nuclei. 300 diameters.” (Public domain, CC BY-NC 4.0) (C) PGCCs in HeLA cell culture indicated by arrows. Multiphoton fluorescence image: cytoskeletal microtubules, magenta; DNA, cyan. (Image by NIH, public domain, CC-PD-Mark)

Figure 2. PubMed queries of the polyploid giant cancer cell literature.

PubMed-listed entries of indicated queries accessed on 05/10/2019. Entries that are listed with multiple search terms are indicated by connecting edges.

Figure 3. Polyploid giant cancer cells in prostate cancer in vivo and in vitro.

(A) H&E image of a lymph node prostate cancer metastasis with PGCCs (one region indicated by yellow border). (B) Phase image of a PC3 PGCC undergoing asymmetric division to form mononuclear and typical-sized daughter cells. PC3 cells were cultured with 10nM Docetaxel for 3 days followed by 4 days in Docetaxel-free media. (scale = 200 um)

Figure 4. Polyploid giant cancer cells are the majority population following docetaxel treatment in vitro.

(A) PC3 cell culture at baseline contains rare PGCCs (arrow). (B) After treatment for 72 hours with LD90 docetaxel, PGCCs are the dominant population and virtually no non-PGCC cells remain. (Phase contrast; scale = 100 um)