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Stem cells, senescence, neosis and self-renewal in cancer

Rengaswami Rajaraman*, Duane L Guernsey, Murali M Rajaraman and Selva R Rajaraman

Cancer Cell International 2006, 6:25  doi:10.1186/1475-2867-6-25

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Denys Wheatley   (2009-02-12 18:45)  Editor CCI: posted on behalf of Katrina Erenpreisa email

Comment on the paper by:

Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR. Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int 2006, Nov 8, 6:25.

Is ‘neosis’ a novel type of cell division?

Jekaterina Erenpreisa

Latvian Biomedical Research and Studies Centre, Ratsupites 1,

Riga, LV-1067, Latvia; katrina@biomed.lu.lv

Regrowth of tumour from giant cells is now a focus of interest due to the hypothesis of ‘neosis’ based on several independent observations. Its authors [1, 2] claim neosis to be a novel cell division, the antithesis of mitotic catastrophe, and simultaneously an origin of transient “stemness” of non-polyploid (small) cells deriving from giant cells. It deserves careful consideration. However, I would like to make several comments.

Neosis is based on independent observations from 1957 to date, from different labs cited in [2]. Endopolyploid cells resulting from prolonged culturing in vitro of normal, virus-infected cells or genotoxically damaged p53-deficient malignant cells are able to produce small-sized descendants by a process which can appear like budding from a disintegrating giant mother. These descendants immediately start mitotic divisions and can form clones. Cells from these clones are transformed [1], but can revert to endopolyploidy, which then produces the next generation of small cells, and so on. Because of the reality of this occurrence and some sceptical responses from readers that it has elicited in some quarters, the process by which the ‘reduction division’ takes place is now being minutely examined.

In a more elaborate variant of the ‘neosis’ hypothesis now offered to us this November [2], a multistep carcinogenesis theory is developed on this basis and its assumptions. It attempts to unite the two recent carcinogenesis paradigms: (i) linking carcinogenesis to accelerated replicative senescence, thereby generating genome instability, aneuploidy and ultimately cancer; and (ii) the origin of cancer from mutant adult stem cells.

The attraction of the ‘neosis’ hypothesis is that it unites these events. It suggests that the offspring budded from senescent giant mother cells inherit aneuploidy and transiently, properties of stem cells. Unfortunately, in their reviews [1,2], the very type of cell division by ‘budding’ is also consequently called by neosis, which is suggested to be a novel and quite different form of division, unlike mitosis and meiosis. Moreover, the authors claim that everyone reporting similar observations has seen ‘neosis’ of the first or the next generation [Table 1 in ref. 2]. For example, regarding Ivanov et al. in their Table 1, we mentioned only mitotic divisions of giant cells and documented symmetric tetrapolar mitosis of an 8C cell.

The cell division facet of the neosis hypothesis is based on the assumption of non-fidelity of such a ‘budding’ mechanism (which is believed to be performed without any rules of segregation of genetic material to daughter cells), and must inevitably lead to aneuploidy in the descendants, and on the secondary assumption that aneuploidy generated in this way is a road to cancer or tumour progression. The main argument is that this division is not like mitosis because the nuclear envelope is preserved and chromosomes are not condensed during budding [1, 2].

It should be commented that, from the biological point of view, it is difficult to imagine an amitotic division segregating polyploid nuclei by the non-fidelity principle may produce descendants with reproductive potential. To believe in this, serious proof must be provided by the authors, and all possible known cell division variants based on fidelity principles would have to be excluded. For example, at least one faithful type of cell division is known in which it occurs within the intact nuclear envelope and without condensed chromosomes, but with the participation of microtubule-organising centres (MTOCs) and the segregation of chromatids to them. It is the most evolutionary primitive and basic form of mitosis called ‘pleuromitosis’ found in protozoans [3]. Extending our initial observations [4] on post-irradiation segregation of mitotic descendents from giant lymphoma cells, which occurs without chromosomes condensation and nuclear membrane dissolution, segregation and activation of MTOCs organising secondary nuclei took place [5]. Another peculiar type of cell division of polyploid cells is also seen in protozoans. Unicellular organisms, Radiolaria, include in their asexual life cycle a cycling polyploidy and hence, a cycling depolyploidisation of a giant cell. Depolyploidisation is occurring by ‘segregation of genomes’ [see Grell, 1953, cited in 3]. Segregation of genomes is preceded by a step of somatic reduction which has common traits with the evolutionary ancestor of meiosis in polyploid protozoans and in cell lines, expression of the principal meiotic genes was found by our group, particularly MOS and Rec8 in irradiated giant cells. However, segregation of genomes is also based on the general rules of the chromosome behaviour in meiosis and mitosis. Moreover, it should not only favour instability of the genome in its polyploidisation phase, but would reduce aneuploidy and mutational load, at a step of somatic reduction [6]. In its way, such a mechanism - although superficially very similar to ‘neosis’ - denies its premises.

References

1. Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R. Neosis: a novel type of cell division in cancer. Cancer Biol Ther 2004, 3: 207-218.

2. Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR. Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int 2006, Nov 8, 6:25.

3. Raikov IB (1982). The protozoan nucleus. Morphology and evolution. Vienna-New York, Springer Verlag.

4. Erenpreisa Je, Cragg M, Fringes B, Sharakhov I, Illidge TM. Release of mitotic descendants by giant cells from irradiated Burkitt lymphoma cell lines. Cell Biol Int 2000, 24: 635-648.

5. Erenpreisa J, Kalejs M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D, Cragg MS, Ivanov A, Illidge TM. Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biol Int, 2005, 29: 1005-1011.

6. Kondrashov AS. The asexual ploidy cycle and the origin of sex. Nature 1994, 370: 213-216.

Competing interests

No competing interests

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Neosis: a unique approach

Denys Wheatley   (2007-02-09 12:29)  Editor CCI email

Comment posted by DNW (Editor CCI) on behalf of Dr Spencer:

I find this article extremely interesting and a novel approach to the realm of cancer research. Too often we are stuck in a rut in terms of theories of how and why something happens, and it is essential that we should take a serious look into alternative ideas. Many times in history what seemed like an odd-ball idea or theory about a concept turned out in the end to be the absolute truth as we know and understand it today (e g. the idea that the sun goes round the earth). It behooves us to take seriously alternative views and ideas to seek the truth of a situation - and in the case of cancer, regarding the effect this disease has on humankind, I believe it is essential that we down any scenario that seems potentially useful in finding an end to it!

I am personally grateful to Dr. Rajaraman for his long, tireless, and exhaustive research along the lines of Neosis and for his conclusions and foresight into how this process could be useful in stopping the disease.

I wish him and his team the best of luck in future endeavors along these lines, and can only hope and pray that others in the field of cancer research searching for a cure will take a serious look at Neosis, such that future studies on this process will lead, in some manner, to a amelioration or even elimination of this disease..

Lawrence Spencer

Researcher and University Professor – Retired

B.Sc. - Biology (Dalhousie Univ.)

M.Sc. - Genetics (Dalhousie Univ.)

Ph.D. - Microbial Genetics (Univ of Toronto)

Lecturer and Professor - (Mount St. Vincent Univ.)

Sales Manager - (Bayer Healthcare Inc., Eastern Canada)

Competing interests

No competing interests

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The neosis idea unites chromosomal instability (CIN) concept with the role of polyploidy/aneuploidy and stem cancer cells' role in tumorigenesis

Denys Wheatley   (2007-02-09 12:28)  Editor CCI email

Comment (posted on behalf of Professor Sikora by DNW (editor CCI):

The transforming events that allow cancer cells to develop are still not fully understood. A number of theories have been proposed. The most accepted view is that cancer results from the accumulation of inherited and somatic mutations in oncogenes and tumor suppressor genes. Mutations in those genes increase the proliferative potential of cells. It is believed that cancer cells are immortal, namely do not undergo senescence. However, the present paradigm is that, not only oncogenes, but also drugs or irradiation can induce senescence of cancer cells. Cancer cells that undergo in vitro senescence became giant and polyploidy and, as hitherto supposed, cease to proliferate. On the other hand, it is thought that polyploidy provides a route to aneuploidy, and thereby contributes to malignancy. However, the mechanisms that generate aneuploid cells are still poorly recognized and understood.

Dr Rajaraman and coauthors claim that giant/polyploid cells have the potential to undergo neosis, namely nuclear budding followed by asymmetric cytokinesis, giving rise to aneuploid cells termed Raju cells. Raju cells are unique in that they transiently display stem cell properties, have inherited genomic instability, have the potential to differentiate into tumor cells and have extended, but, limited mitotic division potential. At the end of their mitotic life span, they repeat the cycle of senescence, neosis and production of the next generation of Raju cells, which repeat the same cycle of events several times through the life of the tumor.

The neosis idea unites very nicely chromosomal instability (CIN) concept with the role of polyploidy/aneuploidy and the role of cancer stem cells in tumorigenesis.

Asymmetric animal cell division by budding has also been described by others, but these works have so far had no repercussions. I am afraid that the prospect of neosis will be also regarded with scepticism until others can verify it. Personally, I like the neosis idea very much, especially since we have got preliminary results proving asymmetric divisions of cancer cells in vitro lead to senescence. When data are completed we hopefully will support Dr Rajaraman’s ideas.

Prof Ewa Sikora,

Nencki Institute of Experimental Biology

Warsaw, Poland

Competing interests

No competing interests

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The editor (DNW) has edited 4 incoming comments on this paper and will post them for the four contributors concerned.

Denys Wheatley   (2007-01-12 18:34)  BioMedES email

Re: Rajaraman et al.- Cancer Cell International 2006,6:25 ID: 246532

Comment 1:

I am a retired cell biology professor from University of New Brunswick, Canada. Even after my retirement I keep up with developments in the area of cell biology. Recently I read with interest an article "Hypothesis: Stem cells, senescence, neosis and self renewal in cancer" by Rajaraman et al. in the November 2006 papers in Cancer Cell International. It is a revolutionary hypothesis of cancer cell biology. This nicely written article is one of the best I have read this year and deserves to be recognized in this respect.

P. Sivasubramanian

psivasub@unb.ca

Comment 2:

Of future critical importance.

I believe the calibre of this work provides a new benchmark for cancer research. It is an insightful new paradigm of future critical importance, and speaks to the plasticity of life at the cellular level which has not yet been appreciated.

(No competing interests)

Robert Cervelli

Origin BioMed Inc.

Comment 3:

Rajaraman R et al. CCI 2006, 6:25. Stem cells, senescence, neosis, and self-renewal in cancer

Genome reduction division of large endopolyploid cells to small cells with reduced genome contents occurs as a constitutive process in mammalian placentas [1,2], which by inference was recently given the non-descriptive name of “neosis” [3]. This unusual type of division has been preserved in the evolutionary records from the more primitive Protista group of animals [4]. This type of reduction division was observed in cell lines as a “neotic” process to genetically altered, small cells with mitotic longevity [3]. However, these latter features of genetic diversity and longevity were only described for reduction division in mouse cell lines that had undergone genotoxic-induction of polyploidization. For human small cells (from both primary cultures and cell lines) the possession of these latter characteristics are very sketchy [5-7]. Another difference between human and mouse cells is that primary human cells must gain telomerase activity for sustained proliferation whereas mouse cells are constitutively positive. However, “neosis” as a process with transient stem cell activities is the suggested course to carcinogenesis and in tumor progression [3].

Recently, a mitotic cycling of endopolyploid cells through diplochromosomes (ie pairs of sister chromosomes) were observed for primary human cells [8]. Cycling of endopolyploid cells was reported for the mosquito as a mitotic reduction division to genome-reduced small cells [9]. Therefore, for human mortal cells the complete story of gross cellular happenings is still a large question. For instance, in addition to a possible mitotic reduction division, cycling polyploidy in itself is suspicious of missegregations to aneuploidy which is considered to be the evolutionary machinery for neoplasia. Thus in further studies on primary human cells it becomes counterindicated to mask the interphase reduction division under the non-descriptive term of “neosis”. This non-self-explanatory word wil confuse the connections and correlations within the literature on similar processes in other organisms. Perhaps a new term might be considered.

References

1) Zybina EV, Zybina TG: Polytene chromosomes in mammalian cells. Int Rev Cytol 1996, 165:53-119.

2) Zybina EV, Zybina TG: Bogdanova MS, Stein GI. Whole-genome chromosome distribution during nuclear fragmentation of giant trophoblast cells of Microtus rossiaemeridionalis studied with the use of gonosomal chromatin arrangement. Cell Biol Int 2005, 29:1066-1070.

3) Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR: Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int 2006, 6:25 (8 Nov. 2006)

4) Erenpreisa J, Kalejs M, Cragg MS: Mitotic catastrophe and endomitosis in tumor cells: An evolutionary key to a molecular solution. Cell Biol Int 2005, 29:1012-1018.

5) Romanov SR, Kozakiewicz BK, Holst CR, Stamfer MR, Haupt IM, Tlsty TD: Normal human mammary cells spontaneously escape senescence and aquire genomic changes. Nature 2001, 409:633-637.

6) Erenpreisa J, Kalesj M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D, Cragg MS, Ivanov A, Illidge TM: Segregation of genomes in polyploidy tumor cells following mitotic catastrophe. Cell Biol Int 2005, 29:1005-1011.

7) Walen KH: Spontaneous cell transformation; karyoplasts derived from multinucleated cells produce new cell growth in senescent epithelial cell cultures. In Vitro Cell Devel Biol - Animal 2004, 40:150-158.

8) Walen KH: Human diploid fibroblast cells in senescence; cycling through polyploidy to mitotic cells. In Vitro Cell Dev Biol – Animal 2006, 42:216-224.

9) Grell SM: Cytological studies in Culex. I. Somatic reduction divisions. Genetics 1946, 31:60-76.

Kirsten H Walen

VRDL, California Department of Health Services, 850 Marina Bay Parkway, Richmond, CA 94801, USA Fax; 510-234-3127; E-mail; kwalen@dhs.ca.go

Comment 4:

Rajarama et al., CCI 2006, Nov 8, 6.25

Is ‘neosis’ a novel type of cell division?

Regrowth of tumour from giant cells is now a focus of interest due to the hypothesis of ‘neosis’ based on several independent observations. Its authors [1, 2] claim neosis to be a novel cell division, the antithesis of mitotic catastrophe, and simultaneously an origin of transient “stemness” of non-polyploid (small) cells deriving from giant cells. It deserves careful consideration.

Here are some initial comments. Neosis is based on independent observations from 1957 to date, from different labs cited in [2]. Endopolyploid cells resulting from prolonged culturing in vitro of normal, virus-infected cells or genotoxically damaged p53-deficient malignant cells are able to produce small-sized descendants by a process which can appear like budding from a disintegrating giant mother. These descendants immediately start mitotic divisions and can form clones. Cells from these clones are transformed [1], but can revert to endopolyploidy, which then produces the next generation of small cells, and so on.

In a more elaborate variant of the ‘neosis’ hypothesis now offered to us this November [2], a multistep carcinogenesis theory is developed on this basis and its assumptions. It attempts to unite the two recent carcinogenesis paradigms: (i) linking carcinogenesis to accelerated replicative senescence, thereby generating genome instability, aneuploidy and ultimately cancer; and (ii) the origin of cancer from mutant adult stem cells.

The attraction of the ‘neosis’ hypothesis is that it unites these events. It suggests that the offspring budded from senescent giant mother cells inherit aneuploidy and transiently, properties of stem cells. Unfortunately, in their reviews [1,2], the very type of cell division by ‘budding’ is also consequently called by neosis, which is suggested to be a novel and quite different form of division, unlike mitosis and meiosis. Moreover, the authors claim that everyone reporting similar observations has seen ‘neosis’ of the first or the next generation [Table 1 in ref. 2]. For example, regarding Ivanov et al. in their Table 1, we mentioned only mitotic divisions of giant cells and documented symmetric tetrapolar mitosis of an 8C cell.

The cell division facet of the neosis hypothesis is based on the assumption of non-fidelity of such a ‘budding’ mechanism (which seems to be performed without any rules of segregation of genetic material to daughter cells), and must inevitably lead to aneuploidy in the descendants, and on the secondary assumption that aneuploidy generated in this way is a road to cancer or tumour progression. The main argument is that this division is not like mitosis because the nuclear envelope is preserved and chromosomes are not condensed during budding [1, 2].

It should be commented that, from the biological point of view, it is difficult to imagine an amitotic division segregating polyploid nuclei by the non-fidelity principle may produce descendants with reproductive potential. To believe in this, serious proof must be provided by the authors, and all possible known cell division variants based on fidelity principles would have to be excluded. For example, at least one faithful type of cell division is known in which it occurs within the intact nuclear envelope and without condensed chromosomes, but with the participation of microtubule-organising centres (MTOCs) and the segregation of chromatids to them. It is the most evolutionary primitive and basic form of mitosis called ‘pleuromitosis’ found in, e.g. protozoans [3]. Extending our initial observations [4] on post-irradiation segregation of mitotic descendents from giant lymphoma cells, which occurs without chromosomes condensation and nuclear membrane dissolution, segregation and activation of MTOCs organising secondary nuclei took place [5]. Another peculiar type of cell division of polyploid cells is also seen in protozoans. Unicellular organisms, Radiolaria, include in their asexual life cycle a cycling polyploidy and hence, a cycling depolyploidisation of a giant cell. Depolyploidisation is occurring by ‘segregation of genomes’ [see Grell, 1953, cited in 3]. Segregation of genomes includes a step of somatic reduction which has common traits with the evolutionary ancestor of meiosis in polyploid protozoans and in cell lines, expression of the principal meiotic genes was found by our group, particularly MOS and Rec8 in irradiated giant cells. Such a life cycle-like process, when borrowed by p53 deficient cells from protozoans, can alternate vegetative and reproductive generations and thus programmatically give rise to stemness. In fact, it is the most fitting biological process describing the given observations from several laboratories. However, segregation of genomes is based on the general rules of the chromosome behaviour in meiosis and mitosis. Moreover, it should not only favour instability of the genome in its polyploidisation phase, but would reduce aneuploidy and mutational load, at a step of somatic reduction [6]. In its way, such a mechanism - although very similar to ‘neosis’ - denies its premises.

References

1. Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R. Neosis: a novel type of cell division in cancer. Cancer Biol Ther 2004, 3: 207-218.

2. Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR. Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int 2006, Nov 8, 6:25.

3. Raikov IB (1982). The protozoan nucleus. Morphology and evolution. Vienna-New York, Springer Verlag.

4. Erenpreisa Je, Cragg M, Fringes B, Sharakhov I, Illidge TM. Release of mitotic descendants by giant cells from irradiated Burkitt lymphoma cell lines. Cell Biol Int 2000, 24: 635-648.

5. Erenpreisa J, Kalejs M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D, Cragg MS, Ivanov A, Illidge TM. Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biol Int, 2005, 29: 1005-1011.

6. Kondrashov AS. The asexual ploidy cycle and the origin of sex. Nature 1994, 370: 213-216.

Jekaterina Erenpreisa

Latvian Biomedical Research and Studies Centre, Riga; katrina@biomed.lu.lv

Competing interests

No competing interests

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