On the 40th anniversary of the International Symposium “The role of stem cells in leukemo- and carcinogenesis”: in Kyiv again

On the eve of the International Symposium “Normal and Cancer Stem Cells: Discovery, Diagnosis and Therapy” to be held in Kyiv, Ukraine on October 4–5, 2017, it would be appropriate in the retrospect of time to remind of the First Symposium “The Role of Stem Cells in Leukemo- and Carcinogenesis”. Forty years ago in 1977, Institute of Oncology Problems (former name of R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobio­logy, the National Academy of Sciences of Ukraine) also became the venue of the scientific meeting, which drew keen interest and was attended by scientists from Great Britain, France, Czechoslovakia, Germany, Hungary, Romania, Ukraine, Russia, Byelorussia. The Conference organized at the initiative of the director and founder of the Institute, academician R. Kavetsky, was preceded by the extensive personal contacts with leading scientists in the field who were finally invited to contribute to this meeting.

The program of that meeting comprised the lectures and reports summarizing the results of the research in the field of stem cells, in particular precursors of hematopoietic and immunocompetent cells, factors of microenvironment and regulation of stem cell proliferation and differentiation in normal development and tumor growth.

These two international conferences are forty years apart. And not only time but striking differences in conceptual background and technological state-of-the-art separate two events. It was not until the 1960s, that the pioneering work by E. McCulloch and J. Till suggesting the existence of hematopoietic stem cell had been appeared. At the time when the first conference in Kyiv was held, hybridoma technology has just broken the ground (G. Kohler and C. Milstein, 1975). Therefore, in 1970s, monoclonals as highly specific reagents were not yet available for studying stem cells. The powerful flow cytometry technology has been also just emerging. In vivo models allowing for grafting normal and leukemic human hematopoietic cells into immune-deficient mice (SCID and NOD/SCID) were not accessible. As a matter of fact, several of the methodological approaches used by the scientists in 1970s to embody their pioneering ideas did not stand the test of time. Nevertheless, some ideas put forward in those early years became very productive for further development of this intriguing field of scientific endeavor.

We may recall in the retrospect of time the centerpiece of several reports presented both by national and foreign scientists who gathered in Kyiv in those early 1970s to discuss the problems of the emerging stem cell science. The abstracts of the First International Symposium were published in 1977. Later the extended texts of the reports were published in a book entitled “Stem Cells and Immunocompetent Cells in Norm and in Tumor Growth” (ed. by Z. Butenko; Kyiv: Naukova Dumka, 1981. 224 p.).

The difficulties in morphological identification of hematopoietic stem cells were discussed by Z. Butenko and K. Zak who presented their original results attempting to describe the peculiar morphological features of these cells. The complex of the techniques having been the best practice at that time was used to describe the morphological features of the candidate hematopoietic stem cells. The results of the studies on the hematopoietic stem cells and precursor cells in spontaneous, induced and transplantable experimental leukemias were later published in the monograph by Z. Butenko “Hematopoietic stem cells and leukemia” (Kyiv: Naukova Dumka, 1978. 179 p.).

E. Frindel presented the data demonstrating that cells of non-cycling population secrete a factor capable of stimulating quiescent stem cells in bone marrow.

R. Petrov et al. made the report “The influence of thymus and aging on the hematopoietic stem cell migration and differentiation”. Applying the clonal technique, morphological and cytogenetic methods which allowed them following up the chromosomal marker, the authors demonstrated the granulocytic differentiation of the hematopoietic precursor cells induced by antigen-stimulated T cells. R. Khaitov et al. demonstrated that migration of stem cells from bone marrow upon vaccination or other antigen challenge is an important step of immunogenesis. The activation of such migration in response to immunization is genetically determined and is not affected by the peculiar features of antigen itself.

The results of the studies presented by A. Fridenstein demonstrated the role of the stromal mechanocytes in providing hematopoietic microenvironment for antigen-dependent stages of differentiation of immunocompetent cells.

I. Chertkov et al. presented the results of ectopic grafting of the bone marrow under renal capsule of irradiated mice. In the ectopic foci of hematopoiesis, hematopoietic cells belonged to recipient, while stroma in such foci was derived from donor. It was also shown that the hybrid resistance to the parental graft mediated by stromal cells was of donor type. Therefore, the regulation of stem cell proliferation was realized by stromal elements of hematopoietic organs. The concept of short-range regulation of hematopoietic stem cells through their microenvironment remains relevant nowadays.

V. Kozlov et al. discussed the problems related to the different levels of regulation of proliferative activity of pluripotent hematopoietic stem cells including cell-to-cell interactions and humoral factors of erythropoietin-type known at that time.

Considerable contribution to understanding the regulation of hematopoietic stem cells was made in the study presented by B. Lord and E. Wright. Both stimulatory and inhibitory factors controlling proliferation of these cells were detected in hematopoietic tissue.

G. Svet-Moldavsky et al. presented the data on the effects of the tumor on the hematopoietic stem cells and angiogenesis. It is worth note that such results later were used in the development of the novel antitumor drugs.

Several reports were devoted to the study of hematopoietic stem cells in experimental leukemias. The Ukrainian scientists R. Kavetsky and Z. Butenko described the changes of bone marrow cells in viral leukemogenesis. The presentation by H. Seidel and U. Opitz dealt with the effects of Rauscher and Friend murine leukemia viruses on different stem cell compartments with the aim of characterizing the target cells for virus and the alterations in stem cell growth and differentiation induced by these viruses.

N. Fedorov suggested that cyclic guanosin-3′,5′-monophosphate may be considered as the important regulator of proliferation and differentiation of hematopoietic stem cells and hematopoietic progenitor cells. The role of this compound in leukemic transformation was also implied.

S. Berceanu et al. observed the differentiation of leukemic blast cells into mature myeloid cells in the explants of leukemic bone marrow from mice. The features of stem cells of Rauscher erythroleukemia strains were discussed in the report by I. Irlin et al.

A. Vorobyev and M. Brylliant made an assumption that sounded revolutionary at that time. They suggested that the cells being at the origin of chronic and acute leukemias (nowadays we would have called them leukemic stem cells) represent the progenitor cells of the major hematopoietic lineages with potential of self-renewal (or even more differentiated cells retaining such potential). The chronic myeloid leukemia, primary myelofibrosis and polycythemia vera represent the neoplasms originating from cells-progenitors of myelopoiesis. Progression of chronic myeloid leukemia in blast crisis is expressed as the shift to the specific types of progenitor cells possessing specific morphological features. And nowadays these cells are well characterized by their immunophenotype. The acute myelomonoblastic leukemia originates from the cells-progenitors of myelopoiesis with limited granulocytic-monocytic differentiation. These ideas were successfully confirmed by laboratory data 30–40 years later (D. Gluzman et al.).

The attention of the participants of the Symposium was also drawn to the reports analyzing the role of stem cells in the initiation of solid tumors. G. Abelev considered the experimental approaches for studying cells-precursors of hepatoma synthesizing alpha-fetoprotein in hepatocarcinogenesis and stem cells in tumors of the liver. K. Pozharissky et al. discussed the role of stem enterocytes in colon carcinogenesis. The authors detected specific glycoprotein analogous to carcinoembryonic antigen in blood serum of the patients with colon cancer.

Many interesting findings were presented also in short reports. Let us list only some of them: L. Seslavina, E. Panteleev “The effects of lymphocyte interaction with allogenic hematopoietic stem cells”; V. Manko et al. “The inhibition of stem cell functional activity by allogenous T and B lymphocytes”; A. Tsutsaeva, A. Goltsev, L. Ostankova “The low temperature (–196 °C) effect on the immunobiological properties of hematopoietic stem cells”; B. Jushkov, A. Barybin “About hematopoietic stem cell properties in experimental leukemia”; V. Pintchouk, V. Kvachjev “On ultrastructural similarity of the “candidates” to hematopoietic stem cells and narrow plasmic B lymphocytes”; V. Chebotatyev “The thymozine influence on stem cells in normal and adrenalectomyzed mice”; L. Pintchouk et al. “The removal of toxic factors in acute leukemia as one possibility of stem cell kinetics action”.

In October 1983, the Second International Symposium “Stem Cells and Tumor Growth” was held in Kyiv. The Symposium focused on the various aspects of the differentiation of stem cells as a unique class of cells capable of self-renewal, their interaction with other cells and extracellular elements of microenvironment, and their role in the origin of neoplasms. The results of the Symposium were summarized in the book “Stem Cells and Tumor Growth” (ed. by V. Pintchouk, Z. Butenko. Kyiv: Naukova Dumka 1985. 256 p.).

Both Symposia in Kyiv have provided the impetus for further studies of stem cells at R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine, in particular the studies of the role of stem cells in leukemo- and carcinogenesis. The results of these studies were regularly published in the scientific periodicals in Ukraine and other countries.

Forty years is quite a long time for scientific endeavors in such challenging area as stem cells and cancer. In fact, the tremendous progress has been made in this field. The stem leukemic cell was first identified followed by the identification of cancer stem cell in several solid cancers. The progress in studying cancer stem cells opens new opportunities for target therapy of malignant diseases. The abstracts of the reports to be presented to the International Symposium “Normal and Cancer Stem Cells: Discovery, Diagnosis and Therapy” (October 4–5, 2017) and the articles published in this issue of “Experimental Oncology” address various aspects of stem cell research including the practical application of stem cell technology.

V.F. Chekhun

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