key: cord-0076843-jgs0cvmt
authors: Kaigorodova, Evgeniya V.; Kozik, Alexey V.; Zavaruev, Ivan S.; Grishchenko, Maxim Yu.
title: Hybrid/Atypical Forms of Circulating Tumor Cells: Current State of the Art
date: 2022-04-08
journal: Biochemistry (Mosc)
DOI: 10.1134/s0006297922040071
sha: a3597532f99e29c87c0c94cf678059e1139a7970
doc_id: 76843
cord_uid: jgs0cvmt

Cancer is one of the most common diseases worldwide, and its treatment is associated with many challenges such as drug and radioresistance and formation of metastases. These difficulties are due to tumor heterogeneity, which has many causes. One may be the cell fusion, a process that is relevant to both physiological (e.g., wound healing) and pathophysiological (cancer and viral infection) processes. This literature review aimed to summarize the existing data on the hybrid/atypical forms of circulating cancer cells and their role in tumor progression. For that, the bioinformatics search in universal databases, such as PubMed, NCBI, and Google Scholar was conducted by using the keywords “hybrid cancer cells”, “cancer cell fusion”, etc. In this review the latest information related to the hybrid tumor cells, theories of their genesis, characteristics of different variants with data from our own researches are presented. Many aspects of the hybrid cell research are still in their infancy. However, with the level of knowledge already accumulated, circulating hybrids such as CAML and CHC could be considered as promising biomarkers of cancerous tumors, and even more as a new approach to cancer treatment.

Currently, cancer is a leading cause of death in the majority of countries. There were 19.3 million of cancer cases in 2020 alone, of which approximately 10 million resulted in death [1] . In the Russian Federation, 591,371 cases of cancer, with 312,122 of deaths were regis tered [2] , which put this disease in the second place based both on occurrence and mortality rates in the country [1] . High mortality rate is determined by numerous unique traits of this disease, including metastatic process [3] and chemoresistance [4] , which are exceptionally important problems of oncology worldwide. It is already known that the fundamentally different group of cells -hybrid cells between the cancerous and healthy cells of the patientplays a role in the abovementioned processes. In this review we will cover the latest information about the form of malignant cells, which recently received close atten tion of the scientists. The theories on formation of hybrids, their types and properties are discussed here together with information from our own research.

Cell fusion is the process opposite to cell division, which entails merging of cell membranes and intracellu lar components belonging to two cells. Osteoclasts, myocytes of skeletal muscles, and syncytiotrophoblast are commonly formed in a human organism under normal conditions via this mechanism. Cell fusion takes place during regeneration of internal organs. Thus, formation of hybrids is involved in several important processes in the human body [5] .

In 1911 Otto Aichel suggested that cancerous cells are able to fuse with leukocytes, creating malignant hybrid cells [5] . His hypothesis was proven in 1974 by Goldenberg et al. [6] . Among the cells of human astro cytic glioma, which were grown inside a golden hamster, BIOCHEMISTRY (Moscow) Vol. 87 No. 4 2022 he found chromosomes, belonging to both donor and recipient. Hybrid cells have the features of both cancer ous cells (unlimited growth and reproduction) and leuko cytes (chemotaxis) [5] . Combination of those character istics makes hybrids quite prone to formation of metasta sis, which was observed by different researchers [7] . The opposite results reported by Harris et al. (1969) and (1989) should be noted [8, 9] . He showed that the fusion of normal mice fibroblasts with different lines of malig nant cells led to formation of the stable hybrids, which had chromosomal biomarkers of both parent cells and did not grow into tumors in histocompatible animals. And despite the fact that currently available data suggest malignant nature of the hybrid cells [10 12] , the study by Harris led to suggestion of existence of the tumor growth suppression genes.

To date, numerous theories have been suggested on the hybrid genesis. The most well researched fusion mechanism among them is the syncytin dependent one (figure, a). In short, this process can be divided into three stages. The first one implies convergence of the mem branes of both cells to the point when there are no water molecules left between the membranes. During that, rearrangement of the negatively charged phospholipids, including phosphatidylserine, from the inner to the outer layer of cell membrane takes place in the location of con tact. Thus, the contents of both outer layers begin to mix with each other, indicating the beginning of the next stage of fusion -hemifusion. Finally, a fusion stalk is formed between the two cells. Its walls are composed of the com bined bilipid layers from both cells. The stalk is filled with cytoplasm of the parent cells. The stalk widens, complet ing the fusion. During this process, the most important tasks such as cell convergence and initiation of fusion are performed by the specific transmembrane proteinsfusogenes, such as syncytin 1 and 2 [13] . Their role in cell hybridization was confirmed numerous times in multiple experiments. For example, in Mezler et al. (2018) work [14] the mesenchymal stem cells (MSC) and SK OV 3 ovarian cancer cells were fused. These cells expressed syn cytin 2 and MFSD 2A on their surface, which under normal condition appear on the syncytiotrophoblast of the healthy placenta. The genes responsible for syncytin synthesis were inserted into the eukaryotic genome by retroviruses millions of years ago. Hence, various viral infections [15] , including SARS CoV 2 [16] , cause hybridization of cells. Some bacteria are also able to cause cell fusion [17] .

Other fusion theories include direct interaction the ory (figure, b), describing exchange of RNA, growth fac tors, and cytokines between the cancer cells and MSCs. Indirect interaction theory (figure, c) explains hybrid genesis with a similar mechanism, but transmission of the molecules is realized via small vesicles, which are released by the cells into extracellular media. Phagocytosis theory implies acquiring of the cancer cell elements by leuko cytes via phagocytosis (figure, d) [18] , including its varia tions, such as entosis (figure, e) -a complete engulfing of one cell by another. During in vitro experiment with MSCs and embryonic stem cells the latter can envelope the mesenchymal stem cells with preservation of their viability [19] . Another variation of phagocytosis involved in the hybridization process is called trogocytosis (figure, f) -"biting" into the cancerous cell with further presentation of antigens belonging to the donor cell on the surface of the recipient cell. In most cases, the donor cell loses its functions by transferring them to the recipi ent cell, or dies. The cell death after trogocytosis is called trogoptosis [20] . Trogocytosis between the MSCs and ovarian cancer cells leading to chemoresistance was described [21] . It is possible that the material of malig nant cells is passed to MSCs not via their direct contact with cancer cells, but by delivery from macrophages, which obtain the components of malignant cells via tro gocytosis. This type of cell interaction is called dragocy tosis (figure, f). Currently it has been confirmed that the specific bacteria species can survive via such mechanism [22] . It was suggested in the Manjunath et al. (2020) review [10] that the transfer of ions, molecules, vesicles, and organelles between the cells can be accomplished by formation of the so called "tunnel nanotubes" (figure, g). These are thin, hollow structures from 20 to 500 nm in diameter, containing F actin and microtubules, which are formed by cells under stress conditions, such as lack of nutrients, viral infections, oxidative stress, etc. Formation of such structures and their attachment to the surround ing cells helps them to survive adverse conditions. Perhaps this is how cancer cells connect with macrophages, which could result in fusion. Finally, the Notch signaling and gap junction could also be involved in the fusion process [21] .

After the fusion hybrid cells undergo the post fusion (or hybrid) selection process (PHSP), which includes spontaneous hetero to synkaryon transitions (HST, tran sition from multinucleated cells to mononucleated cells), chromosomal rearrangements, and mitosis malfunctions. The PHSP is a quite unstable process, which is sensitive to external signals. Failure of the nucleus fusion or of rearrangement of genetic material leads to termination of the fusion process and cell death by apoptosis or necrosis. Because of that, emergence of the viable hybrid cell is a rare event, but in cases of successful selection the result ed cell receives the abilities of uncontrollable growth cou pled with the mechanisms of escaping from cellular immunity and chemoresistance. Such hybrids are able to rapidly multiply and metastasize [23] .

Throughout the study of hybrid cells multiple types of hybrid cells were identified. The main difference between them is the types of parent cells, which join in the course of the fusion process. The data on various types of hybrid cell populations are presented in table.

"Cancer cell + healthy cell" hybrids. This group is the most diverse in comparison with other types of hybrid cells [30 34, 43 45] . The possibility of the tumor cells fusion with epithelial cells [30 33, 45] , fibroblasts [34, 43] , and osteoclasts [44] has been described. Their only common traits include increased resistance to ther apy and higher replication rates. Other characteristics, such as surface markers and typical genetic mutations depend on the parent cells. Inheritance of the stem cells characteristics from the parent cancer cell is often observed, such as appearance of stem cells transcription al factors -Oct4, Sox2, Nanog, Kif4, Bmi1, and CD133, and increase of metastatic potential with mam mosphere formation in breast cancer. In the majority of cases, morphology of the parental cancer cell is also retained by the hybrids. In multiple experiments [31, 32] on fusion of breast epithelial cells with different breast cancer cell lines each formed hybrid showed different capabilities of growth and reproduction. Thus, it is very likely that the hybrid cells contribute significantly to cancer heterogeneity.

Clinical importance of hybrid cells identification is based on the differences in activity of biochemical processes and signaling pathways from conventional malignant cells. For example, the cells produced by fusion with two different breast cancer cell lines exhibited an altered RAF AKT pathway activity. This led to para doxical reaction of the hybrids to PI3K inhibitoradministration of this drug caused significant increase in the malignant cells mobility, while the response of origi nal cancer cells involved migration blockage. This shows importance of detection of hybrid cells in the patients for selection of effective therapy [45] .

"Cancer cell + stem cell" hybrids. Hybrids of cancer cells with stem cells are also quite diverse [11, 41, 42, 46 49] , similarly to the hybrids from the previous group. There is an assumption that hybridization of cancer cells with MSCs or macrophages plays a crucial role in metastatic process, since cancer cells acquire the stem cell properties and become able to circulate in the blood stream. It was shown in Li et al. (2019) experiments [46] that after the fusion of cancer cells with the omental adi pose derived stromal cells (O ASCs), which are similar in their characteristics to MSCs, the resulting hybrid cells exhibited enhanced mobility in comparison with their parental malignant cells. The authors suggested that it was caused by the decrease in E cadherin and increase in vimentin expressions. That was also confirmed in other experiments [41, 42] , where after the fusion of cancerous and stem cells the formed hybrids went through epithe lial mesenchymal transition (EMT) leading to the increase of their proliferative and migratory capabilities. In the process, the newly formed hybrids can either retain morphology of the cancerous epithelial cell [42, 50] or change it to more mesenchymal, fibroblast like appear ance [51] , but in all cases the hybrids have mesenchymal genetic and molecular profiles. The observed tendency of hybrids to aneu and polyploidy and detection of this phenomenon in metastatic cells, as well as the fact that the emergence of tetraploids in non hybrid malignant cells is not common, further confirms this theory [42] .

Probability of the genesis of cancer stem cells (CSCs) through fusion of cancer and stem cells can represented here by hybridomas -artificially grown hybrids between cancerous and plasma cells, which are able to rapid ly synthesize monoclonal antibodies in large quantities; pres ence of such hybrids in oncological patients was not con firmed artificial, irregularly shaped multinucleated cells with short appendages; they are able to present cancer antigens to T cells and stimulate activity of the cytotoxic lymphocytes bet ter than the cancer or dendritic cells; considered as "cancer vaccines"

can retain the cancer cell morphology or take a fibroblast like appearance; keep mesenchymal genetic and molecular profiles; surface markers vary and depend on the parent cells; hybrids display increased mobility, proliferative activity, and therapy resistance; it is assumed that the cancer stem cells not be ruled out. CSCs is a subpopulation of cancer cells with low proliferative potential, but exceptionally high survivability. This is facilitated by their insensitivity to apoptotic signals and resistance to anti cancer drugs. They are playing the role of "sleeping cells", ready to start multiplying even after total eradication of the primary tumor thus causing cancer recurrence. It was shown in numerous studies that hybridization of MSCs and cancer cells produces hybrids with the traits of CSCs. The hybrid theory could explain emergence of this not well known cell subpopulation, but further research to confirm this hypothesis is required [5] . "Cancer cell + macrophage" hybrids. Despite the increased metastatic potential of all abovementioned hybrids, there is no available data confirming their circu lation in blood and other biological fluids, which makes challenging their detection and severely diminishes their diagnostic significance. Instead, a more homogeneous type of hybrid cells can be found in biological fluids -fusions of cancer cells with macrophages. Currently it can be stated that these hybrids represent the most popular object in the hybrid cell research. Several subtypes of such hybrids have already been described, but their similarity should be noted. There is a probability that scientists gave different unique names to the same type of cells. In particular, in 2014 Adams et al. [52] described the cancer associated macrophage like cells, or CAMLs in blood of the patients with breast and pan creatic cancer. Other authors [10] gave the name "Macrophage Tumor cell Fusion cells" (MTF) to the similar cells. Morphologically they are highly differenti ated myeloid cells capable of phagocytosis, with big atyp ical nucleus or with multiple smaller nuclei [52] . The size of CAMLs varies from 21 to 300 μm with average size of 43.5 μm, while the circulating tumor cells (CTC) and leukocytes have sizes of 18.8 and 12.4 μm, respectively [35] . CAMLs are able to take an oval, amorphous, or tad pole like shape [36] . These cells are present in the blood of patients with a broad spectrum of oncological diseases (8.2 cells/7.5 ml) and sometimes in significantly greater quantities such as in ascitic fluid (∼600.000 cells/ml in ovarian cancer patients), and do not appear in the healthy people [53] . CAMLs originate from the tissues of the pri mary tumor -up to 13% of all cells [54] . These cells express CD45, which is common for every human leuko cyte [55] , EpCAM (epithelial cell adhesion molecule), which is found in most epithelial cancer cells [56] , and cytokeratins [57] . Kaigorodova et al. (2020) [58] identi fied 12 different populations of cancer cells in the ascites fluid from ovarian cancer patients. The authors found that the majority of cells were represented by atypical cells with hybrid phenotype, stemness, and evidences of EMT (EpCAM + , CD45 + , CD44 + , CD24 +/-, CD133 +/-, N cadherin +/-). This information was repeatedly confirmed. It was also shown in our studies that the number of atyp ical/hybrid forms of EpCAM + CD45 + cancer cells in ascitic fluid of patients diagnosed with ovarian cancer has a direct correlation with the degree of carcinomatosis [59] . Sukhbaatar et al. (2017) also found EpCAM + CD45 + cells during the search for TP53 mutations in the ovarian cancer cells, but could not find any mutations in this gene in them. The authors showed from 10 to 170 fold increase in the expression of ZEB1, SNAIL, TWIST, INMB1, THNSB, and COL11 genes in CAML, which resulted in the increased amounts of N cadherin and vimentin in these cells [60] .

In addition to CAMLs, small (5 20 μm) round cells with 1 2 round nuclei inside and markers identical to CAML have been detected. These cells were called "cir culating hybrid cells" or CHCs. They were also detected in the blood of oncological patients in numbers far larger than the quantities of CTCs -on average approximately 5 70 cells per 500,000 live cells depending on the type of oncological disease, up to thousands in the cases of uveal melanoma [61] . It was hypothesized that CHCs are the products of cell fusion, when CAMLs are produced as a result of engulfing of cancer cells [57] . A couple of works proves that the metastatic potential of CHCs (in particu lar, it was shown in the study by Gast et al. (2018) [12] ) that the fusion of macrophages with adenocarcinoma and melanoma cells leads to emergence of the hybrid cells with increased proliferative and metastatic potentials. Interestingly, the cells stop their reproduction over time under in vitro conditions. The increased hybrids prolifer ation was detected in vivo, which implies positive connec tion between the "cancer cell + macrophage" hybrids and signals from microenvironment. Even more curious is the fact that CHCs are present even in the blood of healthy individuals, what fundamentally differentiate them from CAML [7] . Heterogeneity of CHCs in expression of the genes responsible for mesenchymal (vimentin, E cad herin), stem properties (CD44, CD133, ALDH1), and some receptors (androgen receptor, AR) has been report ed. Only CHCs with strong mesenchymal and stem prop erties are involved in metastatic process, and the increased AR expression in breast cancer indicates increased resistance to therapy [62 64] .

Cells with CD163 [65 67], CD204, and CD206 [68] were detected repeatedly among the "cancer cell + macrophage" hybrids. These markers are specific to M2 macrophages. Contrary to the pro inflammatory M1 macrophages, M2 cells inhibit inflammation and stimulate the processes of cancer growth and progres sion. It was found that only after the fusion of a cancer cell with an M2 macrophage the resulting hybrid acquires the properties of stem cell and macrophage, thus obtaining increased metastatic capabilities [69] . More than that, a selective fusion of M2 macrophages with cancer cells has been observed [70] . The "cancer cell + macrophage" hybrids are likely to originate from the fusion with tumor associated macrophages (TAMs) -macrophages in the composition of solid tumors that maintain its viability. They have a M2 like phenotype, and it has been suggested that TAMs and M2 macrophages are the same cells, though the latest research speaks the opposite [71] .

The "cancer cell + macrophage" hybrids attract an exceptionally high interest of the scientific community due to their presence in blood in significant quantities even at the earliest stages of the disease [10] and ease of obtaining. Potentially it makes them an efficient and reli able biomarker of solid tumors. Enormous size of CAMLs significantly simplifies the task of isolation of these hybrids, allowing to use technically simple methods, such as microfiltration [35] .

In the recent studies it has been suggested that the EpCAM + CD45 + cells exhibit increased malignancy and chemotherapy resistance. In particular, it is considered that these cells excessively express HLA I and HLA II on their surface, which helps them to escape NK cells. Regarding chemoresistance, CAMLs show increased resistance to, for example, cisplatin and paclitaxel (more than 27 μg/ml, comparing to 8 12 and 7 10 for CD45 -EpCAM + cells, respectively) [52, 72, 73] , and to radiotherapy due to elevated DNA repair capabili ties [66, 74] .

The fact of tumor malignancy itself could be estab lished by the presence of CAMLs. In Adams et al. (2016) research [75] these hybrids were detected in 88% of the patients with invasive breast carcinoma, and only in 26% -with benign growths. Many authors consider direct correlation between the concentration of hybrid cells and patient's outcome. But, despite the significant increase in CD45 + EpCAM + cells concentrations in the latter stages of disease, their presence was also observed in the earlier stages [57] . Presence of these cells long before the development of metastases was described, which like ly makes them a precursor of the tumor upcoming dis semination [10] . Thus, in our latest research it was shown that the atypical/hybrid forms of EpCAM + CD45 + cancer cells could already be detected in the blood of the patients with endometrial cancer at T1 stage. Their number corre lates with the risk of recurrence after treatment [76] . Based on examination of the patients with esopha gus [35] , lung [77] , pancreatic [78] , and other cancers [53] , it was revealed that the CAML size of ≥50 μg and their concentration in blood of ≥5 6 cell/7.5 ml is associ ated with low survivability and high risk of recurrence after therapy. During the simultaneous analysis of CAML and CTCs levels it was demonstrated that the patients with increased amounts of both types of cells in blood (≥5 CTCs/7.5 ml) had lower chances of survival in com parison with the patients with only elevated levels of CTCs [79] .

CHCs themselves also serve as valuable biomarkers in cancer diagnostics and monitoring, not only due to their high concentrations in the patient's blood [80 82 ]. It was established in different studies of the patients with various gastrointestinal cancers [80, 82] that there was a decrease in the levels of hybrids in blood after chemother apy. Increase of the CHCs concentration in blood of the patients with oral carcinomas allowed Henn et al. (2021) predicting the emergence of hidden metastases in lymph nodes, thus providing an opportunity to avoid the highly invasive neck dissection, which leads to complications in 25% of the cases [81] .

An important problem on the path of CHCs to the status of clinical biomarker is their similarity with normal leukocytes of the patient. Because of that, a fast, simple, and efficient isolation of these hybrids and their following analysis is complicated. One of the developing methods for overcoming this issue is dielectrophoretic separation in a specifically designed microfluidic chip. Separation of the cells occurs due to their differences in polarization of each cell and forces of the fluid flow. In the experiment with blood samples from the patients with pancreatic ade nocarcinoma the possibility to increase concentration of CHCs 18.6 fold by excluding 96.5% of leukocytes from the sample was demonstrated [83] .

Evidence of the role of hybrids in cancer spread and drug resistance shows the possibility of developing effi cient cancer treatment strategies targeting hybrid cells. The most obvious approach here seems to be blocking the fusion process itself. It is known that hypoxia and TNFα stimulate cell fusion [84] . They are also involved in apop tosis induction. Scientists confirmed the role of this type of programmed cell death in emergence of hybrids. Hence, it seems possible to suppress cell fusion through inhibition of one or another element of the signaling pathways involved in apoptosis. There is a sufficient amount of research in this field. For example, it is possi ble to disrupt the TNFα receptor function by siRNA [85] or minocycline antibiotic [86] . The well known and actively developing method of halting TNFα synthesis from its precursor pro TNFα is inhibition of the ADAM17 enzyme [87] . Creation of monoclonal antibod ies targeting TNFα or apoptotic pathways is also quite popular [88] . Other targets for apoptosis inhibition are phosphatidylserine [89] , MMP9 [90] , caspases [91] , etc. Some of the described here approaches for anti TNFα therapy appeared in the arsenals of oncologists long ago, but evaluation of the role of this factor in cell fusion could increase their acceptance among doctors.

The role of stimulating factors was also proven by the fact that they are characteristic for inflammation that accompanies both tissue regeneration and cancer pro gression. In both cases, cell fusion is present [92] . Hence, the anti inflammatory therapy could also help in stopping hybridization of cancer cells as was demonstrated, for example, in the experiment conducted by Li [93] , where successful blocking of IL 4 receptors in the rhabdomyosarcoma cells prevented cancer growth and progression in vivo.

Another technique of cell fusion prevention is by dis rupting syncytins' function. Different authors used anti sense nucleotides and small hairpin RNA for inhibition of the syncytin 1 and 2 genes expression, respectively. At the same time, association between the syncytin expres sion and positive outcome for the patients with breast cancer was reported, thus, relevance of such therapeutic approach requires additional research [94] .

Naturally, if something stimulates cell fusion, physi ological inhibitors of hybridization also should exist. It was shown that TGFβ in large quantities suppresses cell fusion, but it could not be considered as an anti cancer drug due to its effect of stimulation of cell proliferation, including malignant ones [95] .

The hybrids between cancer and dendritic cells (DCs) should be covered here separately [40, 96, 97] . These are artificially created cells with antigens belonging to cancer and antigen presenting cells simulta neously. This allows such hybrids to effectively stimulate the patient's own anti cancer immune system. The possi bility of using the hybrids of a cancer cell with a DC was described long ago [40] . Numerous methods using such cells in cancer treatment are currently under develop ment. One of such approach is based on the zirconium metal organic frameworks nanoparticles, which are com monly used for photodynamic therapy, coated by the hybrid cell membranes. After their injection into the bloodstream of a patient, they accumulate in tumors via the enhanced permeability and retention effect (EPR) and presence of cancer cell proteins on the nanoparticle surface. The metal organic framework nanoparticles gen erate a significant amount of reactive oxygen species under the laser irradiation, and antigens from the cancer and dendritic cells on the nanoparticle surface stimulate strong immune response from T killers. In vivo experi ments with mice with inoculated and grown tumors showed a considerable reduction in the tumor growth rates on the 28th day after the start of the therapy in com parison with the effect of other nanoparticles used for photodynamic therapy. On the 62th day 40% survival among the animals in the "nanoparticle + hybrid cell membrane" experiment group was achieved, while in other groups all the mice died [97] .

Despite the fact that the phenomenon of cell fusion was discovered more than 100 years ago, all this time it was mostly out of the sight of researchers -all the atten tion of the scientific community was on the CSCs theory. That is why many aspects of the hybrid cell research are still in the early stages of development. Nevertheless, even at the present level of knowledge, the circulating hybrids, such as CAML and CHCs, are considered as promising biomarkers of cancer, and even more -as a new approach to cancer therapy. Emergence of such novel techniques indicates that there is a large, uncovered potential of hybrid cells requiring extensive research.

Funding. This research was supported by the Russian Science Foundation (grant no. 19 75 30016) .

Ethics declarations. The authors declare no conflicts of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

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