Progression of cancer

Carcinoma constitution originates in the hetero-duplication mitoses (4) which divide non-maturable stem cells into two different types of daughter cells: maturable and non-maturable cancerous stem cells. Throughout the progression of such mitoses, the organoid continuity of the cancer depends only on the non-maturable daughter stem cells, not on the maturable ones. This type of cancer can be considered non-progressive or to be in the incubation stage, as it only enables cancer tissue to preserve its organoid continuity without allowing progressive growth. However, when an occasional mitotic phase of the hetero-duplication mitotic progression undergoes genuine cell-phase duplication mitosis, this non-progressive or incubation stage of cancer is converted to a progressive type of cancer. This conversion is dependent on the reappearance of the complete mitotic condition of the mitotic maturation promoting system (MMPS) containing an abnormal supplement. Thus, a thorough investigation of the abnormal supplement and the reappearance of the complete mitotic condition is an essential part of research efforts to prevent and eradicate cancer.     

Hetero-duplication type of cancerous mitosis

In normal mitosis, the two daughter cells are identical to each other. However, in the case of duplication mitosis of the non-maturable cancerous stem cell, the two daughter stem cells must be non-visually, but certainly different from each other in order to allow for the characteristic type of cancerous cell turnover development. One of these daughter stem cells is maturable and normally activated by the maturation factor, then undergoes maturation mitosis and finally passes through its lifespan. However, the other daughter stem cell is non-maturable and not activated by the maturation factor. It undergoes the original mitosis again, reproducing two daughter stem cells that differ from each other: the above maturable cell and the original non-maturable cell (Fig.). Such a hetero-duplication type of mitosis is peculiar to carcinoma and responsible for the oncogenesis. The origin of this mitosis is most probably an unequal division of a mitotic maturation promoting system (MMPS) at the mitotic phase, and may be dependent on some abnormal supplement of the MMPS. Thus, therapy aimed at the complete eradication of cancer should focus on removal of this supplement from the cancerous cell.     

Cancerous genetic peculiarities non-responsible for cancer development

Certain genetic peculiarities recently identified in cancer cells have generally been regarded as the abnormalities responsible for cancer development. However, these abnormalities may also be found in maturable cancer cells and are not limited only to the non-maturable type. As previously described by the authors, cancer tissue consists of two types of cancerous cells: maturable and non-maturable. The development of cancer may be dependent only on the non-maturable cancerous stem cells, not on the maturable type. Since the non-maturable cell may be solely responsible for carcinogenesis, the relevant genetic peculiarities that are also found in the maturable cancer cells should not be regarded as the abnormalities responsible for carcinogenesis.     

Physio-mitotic theory and a new concept of cancer development

In the physio-mitotic theory, general mitosis consists of two different types: maturation and duplication. While being co-regulated by mechanisms involving maturation and duplication factors, these two types of mitotic activities each play a respective role in the antagonistic histological development of the other. According to the theory of systematic organization, each type of organic tissue is always developed and established under certain physiological conditions. As an organoid tissue, cancerous tissue must also fundamentally develop according to that theory. Consequently, a new concept of cancer development should be devised based on the physio-mitotic theory.     

Physio-mitotic theory and a new concept of leukemia development

In the physio-mitotic theory described previously by the authors (10), general mitosis consists of two different types: essential duplication and converted maturation. These two types of mitosis are regulated by mechanisms involving maturation and duplication factors, and each plays a role in the antagonistic histological development of the other.According to this theory, every kind of leukocyte is produced through mitosis in the bone marrow and migrates during cell turnover to the bloodstream. However, in leukemia a highly excessive number of leukocytes and leuko-blastocysts appear in the bloodstream. This excessive amount is greater than the physiological capability of cells in the bone marrow alone. Such an extremely large group of cells would not be produced without being dependent on an extremely high ratio of produced leukocytes to original stem cells.This extremely high ratio may be due to a systematic pathological deterioration of the mitotic maturation ability during the maturation process of the leuko-blastocysts. Consequently, restoration of the deterioration to the original mitotic maturation response of the normal leuko-blastocysts may be an essential event in achieving leukemia eradication, rather than persistent destruction of individual leukemic leukocytes.     

Duplication mitosis in epithelio-glandular tissue.

As duplication mitosis occurs in epithelio-glandular tissue, a different concept of histological continuity and organization of this tissue is needed. In epithelio-glandular tissue, duplication mitosis play a role in histological continuity, while maturation mitosis leads to histological organization. Duplication mitosis reproduces stem cells for the cell turnover process. The life-span of the cell copies is limited to a certain period by maturation mitosis. Conservation of duplication mitosis and its alteration to maturation mitosis are regulated by a histological mechanism in the gland crypt, involving duplication and maturation factors. The result is that epithelio-glandular tissue is maintained within a prescribed physiological volume without excessive multiplication.     

Duplication mitosis in carcinoma.

As proposed in 'Duplication mitosis in epithelio-glandular tissue' (1), histological continuity is dependent on duplication mitosis. Organoid continuity of carcinomas is also likely to be dependent on duplication mitosis. Cancerous duplication may be due to deterioration of the maturation capacity of carcinoma cells and caused by a cellular abnormality that rejects the effect of the maturation factor. The fundamental therapeutic approach to carcinoma should be altered from one of cell destruction to one of inducing cell-phase maturation.     

Fundamental physio-mitotic theory

In differentiation division, the mitosis occurring within all tissues consists of more than one type of mitosis. It occurs as two antagonistic types: the essential duplication mitosis activated by the effect of duplication factor and the antagonistic maturation mitosis which develops from the essential type and is further stimulated by maturation factor. These different types of mitosis play antagonistic roles in histological development, while maintaining a specified physio-mitotic balance through their respective mitotic factors and mitotic regulatory mechanisms in the tissues. Depending on the physio-mitotic balance between duplication and maturation mitosis, each layer of organized tissue, comprised of intrinsic functional cells, differentiates from one of the three germ layers, without errors that create abnormal characteristics. In this way, the tissues establish histological identity and continuity while maintaining a prescribed histological organization without excess or reduced multiplication within the tissues. This forms the fundamental basis of the physio-mitotic theory.     

MORPHOLOGICAL CHANGES OF MYOFIBRIL IN THE CARCINOGENETIC COURSE OF 20-METHYLCHOLANTHRENE-INDUCED RHABDOMYOSARCOMA

In this study 20-methylcholanthrene (MC) was embedded in skeletal muscle tissue of mice. The resulting morphological changes were observed by light and electron microscope until the occurrence of rhabdomyosarcoma. The injected region of the muscle tissue in which MC was embedded went through three stages: destruction and degeneration, repair, and appearance of atypical cells. The morphologic figures of the myofibrils seen in the skeletal muscle cell during destruction and degeneration were similar to those observable in diseased human muscle, and were interpreted as nonspecific. The muscle tissue then regenerated in the same manner as seen during experimentally induced muscle tissue regeneration in both humans and animals. Abnormal mitotic figures were found 60 to 70 days after the injection of MC. Immature muscle cells, with tuft-formed myofibrils present, underwent abnormal mitosis in which one of the nuclei divided. The rhabdomyosarcoma cells produced by this abnormal mitosis began to appear in the lesion 70 days after the initial embedding of MC. The rhabdomyosarcoma cells in the induced tumor formed undifferentiated myofibrils in various degrees of maturation, and were therefore considered to play a part in the abnormal myofibrillar formation.     

Cell dynamics in the olfactory epithelium of the tiger salamander: a morphometric analysis

Summary The factors controlling neurogenesis and differentiation of olfactory receptor cells in adults are poorly understood, although it is often stated that these cells undergo continual turnover after a pre-determined lifespan. An interesting model in which to study mechanisms which control olfactory receptor neurogenesis and cell turnover is the tiger salamander, since basal cell mitosis varies with epithelial thickness and location in the nasal cavity. This paper presents a quantitative light-microscopic study of the different cell types within the ventral olfactory epithelium of the tiger salamander using a computer-assisted morphometric analysis of 2 m sections. The results show that the surface density of olfactory vesicles remained constant throughout most of the epithelium and was independent of nasal cavity location, epithelial thickness and the total number of nuclei per unit epithelial surface area. Histological classification of nuclei into different cell types indicated that the increase in total cell number with epithelial thickness was mainly due to an increase in the number of immature receptor cells since the number of supporting cells varied only slightly and the numbers of basal cells and mature receptor cells remained constant except in the thinnest, most caudally located epithelium. It is concluded that the rate of maturation of receptor cells may be limited by an optimal surface density of olfactory vesicles. That is, when this density reaches 4.5×10⁴ vesicles per mm² there is a physical or chemical mechanism which prevents the final maturation of newly developing receptor cells, leading to their accumulation. This mechanism may also account for the variations in basal cell mitosis in this species.     

Physio-mitotic theory and a new concept of embryological differentiation

According to the physio-mitotic theory described previously by the authors (10,11), general mitosis consists of two different types: essential duplication and converted maturation. In general embryological differentiation, progression for the most fundamental blastocysts of the three germ layers to the immature stem cells comprising functional organic tissues is dependent on the essential duplication mitosis. This mitosis replicates stem cells while gradually initiating latent cellularities whereas the converted maturation process merely amplifies these latent cellularlities by maturing the basic cells in differentiated functional end cells with a pre-determined life span. The differentiation from the three-germ layer to embryologically organized tissues is dependent on duplication mitosis while being regulated by interactions with maturation mitosis. Thus, the complicated embryonic differentiation must be established in each type of organic tissue. During the process, these two types of mitosiseach play an antagonistic role in the embryological development of the other. This is another application of the physio-mitotic theory.     

Neoplasia--a stem cell pathology

Cell proliferation in the organism is accompanied by cell displacement. Proliferating tissues exhibit three key characteristics: a site of origin of the stem cell, a tissue radius along which all constituents except the stem cell are displaced and a periphery where cells are eliminated. The tissue thus consists of two cell types: Stem and transitional. Since only the first resides permanently in the tissue any lasting change observed in the tissue is directed by the stem cell. Each stem cell division results in two cell types: one replacing the parent cell to remain a stem cell, while the other originates an outward displaced transitional cell clone whose life span is limited. In the normal state, the stem cell pool is constant, although its replenishment capacity is limited. Neoplasia is regarded here as a purposeful tissue alteration originating in a stem cell change manifested by: Aneuploidy, maturation arrest, stem cell pool enlargement and increasing cell turnover. Stem cells are assumed to secrete a substance 'A' necessary for a proper tissue function, whose production is impeded by carcinogens, mainly by stem cell depletion. Since however stem cell replenishment is limited, the organism grows a specialized organ, the neoplasm, producing a less efficient substitute for 'A', denominated here as substance 'B'. Neoplastic growth is indirectly dependent upon the abundance of substance 'A', the supply of which should be followed by a reduction of neoplastic mass. Neoplasia is thus viewed here as a protective function directed by the stem cell and linked with "oncogenes". Each determined stem cell is harbouring a specific oncogene and exhibits a typical neoplasm. Since the theory predicts that neoplastic growth indirectly depends upon the abundance of substance 'A', it may be tested by investigating the effect of substance 'A' producing stem cells upon the growing neoplasm. Their supply to the organism should be followed by a reduction of the neoplastic mass.     

Intestinal graft versus host disease.

An ileocolectomy specimen was examined from a patient with graft versus host disease (GvHD). In addition to the characteristic histological features of this condition, both the small and the large intestine showed extensive destruction of mucosal tissue with survival of clusters of enterochromaffin cells. This appearance has previously been described only in the large bowel. Endocrine cells seem to be less vulnerable to the effects of GvHD than epithelial cells, resulting in their being spared, which is not seen in other types of crypt destruction.     

Leukemia eradication and the effect of maturation factor

As described previously (1), the development of leukemia might be attributable to the deteriorated effect of a maturation factor on the relevant type of the leukemic leukocytes, rather than a certain cellular defect initiated in the individual leukemic leukocytes. Thus, the eradication of the leukemia should depend on re-establishing the effect of the maturation factor, rather than persistent destruction of individual leukemia leukocytes. The most powerful effect of the maturation factor may be exerted throughout the mitotic duplication process of the most immature fibro-blastocysts in an in vitro cell culture. Thus, to achieve leukemia eradication, this specific cell culture, which might indefinitely be duplicating the immature fibro-blastocysts in the lineage of leukemic leukocytes, should be investigated and developed. Additionally, a technical method of extracting the maturation factor for the maturation mitosis of leukemic leukocytes should be devised and developed in the future.     

Pluripotent Stem Cells for Retinal Tissue Engineering: Current Status and Future Prospects

The retina is a very fine and layered neural tissue, which vitally depends on the preservation of cells, structure, connectivity and vasculature to maintain vision. There is an urgent need to find technical and biological solutions to major challenges associated with functional replacement of retinal cells. The major unmet challenges include generating sufficient numbers of specific cell types, achieving functional integration of transplanted cells, especially photoreceptors, and surgical delivery of retinal cells or tissue without triggering immune responses, inflammation and/or remodeling. The advances of regenerative medicine enabled generation of three-dimensional tissues (organoids), partially recreating the anatomical structure, biological complexity and physiology of several tissues, which are important targets for stem cell replacement therapies. Derivation of retinal tissue in a dish creates new opportunities for cell replacement therapies of blindness and addresses the need to preserve retinal architecture to restore vision. Retinal cell therapies aimed at preserving and improving vision have achieved many improvements in the past ten years. Retinal organoid technologies provide a number of solutions to technical and biological challenges associated with functional replacement of retinal cells to achieve long-term vision restoration. Our review summarizes the progress in cell therapies of retina, with focus on human pluripotent stem cell-derived retinal tissue, and critically evaluates the potential of retinal organoid approaches to solve a major unmet clinical need—retinal repair and vision restoration in conditions caused by retinal degeneration and traumatic ocular injuries. We also analyze obstacles in commercialization of retinal organoid technology for clinical application.     

Genetic mosaicism and the control of cancer.

The susceptibility of animal cells to certain lethal agents, including a variety of cytotoxic drugs, is genetically determined; cells which are otherwise identical may therefore differ in terms of which agents are lethal for them. If such genetic diversity existed within a tissue, exposure to any of these lethal agents would not destroy every cell, but only that fraction of the population that was susceptible. In contrast, if a clone of malignant cells arose from any single cell within such a tissue, the entire malignant clone should be susceptible to destruction by whatever agent its progenitor cells was susceptible to. Treatment of a tumor in a host whose tissues displayed such genetic mosaicism might therefore possess the potential for destroying all tumor cells, at the cost of destroying only a fraction of the normal cells. Prophylactic induction of such mosaicism in normal hosts by genetic manipulation represents a potential future strategy for cancer control. Evidence is presented suggesting that women heterozygous for deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-transferase may constitute naturally occurring examples of such exploitable mosaicism.     

Studies on phage development. II. The maturation of T4 phage in the presence of puromycin

Maturation of T4 can proceed in the presence of 5-methyltryptophan or puromycin. Puromycin inhibits phage protein synthesis within a few seconds, thus limiting the amount of phage precursor material available for maturation. After the arrest of protein synthesis, maturation continues unabated until the limiting protein precursor is depleted. At least one protein, the tail fiber protein, is depleted. Phage protein maturable in the presence of puromycin appears about 5 minutes before maturation begins. The level of the maturable material reaches a maximum at the beginning of maturation. This level is taken as a measure of the size of the pool of complete sets of maturable phage protein. The bulk precursor protein begins to accumulate 3 minutes earlier than serum blocking proteins (SBP) and forms a pool about twice as large as the pool of SBP.     

Evaluation of neoplastic human mast cells by tryptase-immunoelectron microscopy

AIMS: To analyse and characterize the ultrastructural morphology of normal tissue mast cells (MC) and neoplastic bone marrow MC. METHODS: We have examined the ultrastructure and cytomorphological features of MC derived from cord blood cells, neoplastic bone marrow MC in patients with systemic mastocytosis (SM, n = 4), myelomastocytic leukaemia (MML, n = 2), mast cell leukaemia (MCL, n = 2) and tryptase-positive acute myeloid leukaemia (AML, n = 4). RESULTS: Based on their ultrastructure and morphology, four distinct cell types could be delineated: (i) mature well-granulated tissue MC exhibiting a round central nucleus; (ii) atypical MC type I with oval nuclei, hypogranulated cytoplasm, and prominent surface projections; (iii) immature atypical MC with bi- or polylobed nuclei (atypical MC type II = promastocytes); and (iv) metachromatic blasts. Type I atypical MC were detected in a patient with indolent SM, whereas type II MC and metachromatic blasts were primarily found in MML, MCL and tryptase-positive AML. In all samples examined, the identity of MC could be reconfirmed by immunoelectron microscopy, irrespective of the stage of cell maturation or the disease variant, all types of MC contained tryptase in their cytoplasmic granules. CONCLUSION: Immunoelectron microscopy may be a helpful approach in confirming the identity of neoplastic MC in myeloid neoplasms.     

An etiologic model proposing that sporadic adult-onset carcinoma is extramedullary hematopoiesis

This model proposes that primary carcinomatous tumors and almost all metastases are extramedullary hematopoietic tissue formed to compensate for reduced hematopoietic activity in the bone marrow. These marrow lesions are currently considered to be metastatic in origin, but as fibrosis and sclerosis are identifying features they are here equated to myelofibrosis. Myelofibrotic marrow is characterized by an increase in the number and size of vascular sinusoids. The increased blood flow suggested by this morphology, and observed in myelofibrosis patients, causes a rise in marrow pressure which may trigger the fibrosis. Specific carcinoma morphologies are equated to stages in endochondral bone and marrow formation and, as such, cancer cell identity varies with morphology. For example, infiltrating carcinomas of the breast consist of collagen and mucoid secreting cells in single file formation. This morphology is equated to the cartilagenous stage of marrow formation, when mesenchymal stem cells proliferate and differentiate into chondroblasts. In this model "infiltrating" cells arise in situ from stem cells located in the connective tissue. Tubular breast carcinoma, with its single layer of osteoblast-like carcinoma cells encircling small lumens and long branching tubules, is equated to the trabecular stage of marrow formation during which osteoblasts surround small pieces of calcified cartilage and begin secreting osteoid that will form the trabeculae. Lobular carcinoma in situ consists of cancer cell clusters separated by narrow clear spaces that, under high magnification, appear vascular. This morphology is equated to hematopoietic tissue in which primitive hematopoietic cells lie between anastomosing sinusoids. Similar cartilagenous, trabecular and hematopoietic morphologies can be found in carcinomatous tumors of most organs, but the nomenclature is variable. The hematopoietic carcinomas share numerous features with hematopoietic tissue including a structure composed of intermingled normoxic and hypoxic regions and a metabolism characterized by elevated levels of glycolysis. They also contain similar proportions of clonal cells. If this model is correct it necessitates a change in the treatment of carcinoma. If cancer cells are not the enemy, but desperately needed immature blood cells, and the medical problem is not the presence of tumors, but the inefficiency of this extramedullary hematopoietic tissue, then treatment should focus on increasing marrow hematopoiesis. As evidence suggests that the marrow lesion is the result of increased hydrostatic pressure this could be done by reducing blood volume. One way to accomplish this may be through the ingestion of ephedrine, as it is hypothesized to increase vascular tone.     

Multiplication and differentiation of glial cells in the optic nerve of the postnatal rat. A reassessment

In order to establish a firm basis for our studies on cell reactivity during Wallerian degeneration in the optic nerve of the rat, gliogenesis in this fiber tract was reassessed. Rats aged 2, 5, 8 and 20 days (key-stages) received a single injection of tritiated thymidine and were sacrificed after a survival period of 1, 3, 5, 10 and 20 days. Before the 5th postnatal day, glioblasts and astrocytes are the only cell types identifiable in the optic nerve. Most of astrocytes undergo their last mitosis during this period. Oligodendrocytes are first seen after the 5th postnatal day, and their maturation proceeds through a regular sequence of light, medium and dark cells. Detailed analysis of this time-course reveals that those precursors of oligodendrocytes that undergo last mitosis at the 5th postnatal day are retarded in their differentiation as compared with those undergoing their last mitosis during the 6-8 days period. When considering glio-axonal interactions, the onset of oligodendrocyte differentiation could proceed in two phases, especially at the 5 day key-stage, with an initial signal triggering the cessation of mitosis of glioblasts and a second signal inducing their maturation, conditioned by the type of surrounding tissue.