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.

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

“…As pointed out by Amend et al [23], the observation that a tumor is comprised of multiple cancer cell sub-populations with different sizes and ploidy (intratumor heterogeneity) was first reported over a century ago (in the mid 1800s) by scientists who were equipped with only a simple (light) microscope, and often with no camera. Unfortunately, the importance of such observations went largely unnoticed by the majority of the scientific community, perhaps because of the development and widespread use of state-of-the-art high-throughput assays that generate averaged results for a population of cells.…”

“…Of the many types of cancer cell misbehavior, dormancy, a type of active sleep, presents a major obstacle in the medical treatment of malignant solid tumors [19][20][21][22]. A subset of dormant cells are considered "giants" and contain either multiple nuclei or a highly enlarged nucleus (sometimes >100 fold) when compared to the nucleus of the bulk of cancer cells within the same tumor [23][24][25][26][27][28][29][30]. Such cells are referred to as polyploid giant cancer cells (PGCCs).…”

“…Consistent with these properties, a significant number of recent reports with different biological systems (e.g., tumor-derived cell lines, animal models, and specimens from cancer patients) have underscored the key roles played by PGCCs in tumorigenesis, metastasis, and disease relapse after conventional cancer treatments. The contributions that PGCCs make to therapy resistance is demonstrated for various types of solid tumors, including ovarian cancer [43,44], prostate cancer [23,47], brain cancer [26,28], renal cancer [54], colon cancer [46], and breast cancer [45,55], including the most aggressive form (triple negative) [55] for which chemotherapy remains the cornerstone therapeutic. There have been several reviews on the formation, stemness, and tumorigenicity of PGCCs before and after exposure to cancer therapeutic agents (e.g., [56][57][58][59]).…”

Tamoxifen is a candidate first‐in‐class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells—Unrecognized players in tumorigenesis

“…This study aims to address the only recently recognized clinical need to prevent PGCC offspring and cancer recurrence . A 2019 study demonstrated that ASAH1 is required for generation of PGCC progeny and we hypothesized that ASAH1 inhibition could be an effective maintenance therapy when a first course of treatment results in apparent cancer remission .…”

Invasion of homogeneous and polyploid populations in nutrient-limiting environments

“…Tetraploid cells resulting from WGD often lose regions of the genome, giving rise to poly-aneuploid cancer cells (PACCs). Multiple studies have described a minority population of PACCS with an unusual resilience to stress [19][20][21]. A very recent investigation of evolutionary selection pressures for WGD suggests that it mitigates the accumulation of deleterious somatic alterations [22].…”