Basis Of Cellular Differentiation Research Articles

Epigenetics in Mammary Gland Biology and Cancer

In the post genome era, the focus has shifted to understanding the mechanisms that regulate the interpretation of the genetic code. “Epigenetics” as a research field is taking center stage. Epigenetics is a term which is now being used throughout the scientific community in different contexts from physiology to cell biology and genetics with diverse meanings inherited from the past [1]. The term “Epigenetic” was first coined in the nineteen forties by C.H. Waddington when he proposed the concept of the “Epigenetic landscape” for the process of cellular decision-making during development [2, 3]. He developed this concept by taking into account heterogeneous data from genetics, evolutionary biology, and embryology, providing a conceptual model of the interaction of genetic material with its surroundings to produce a phenotype. Since then, the concept of epigenetics has evolved. It is now often defined as “the manifestation of a phenotype, which can be transmitted to the next generation of cells or individual, without alterations to the DNA sequence (genotype)”. An epigenetic event is a cell’s or organism’s response to external queues, which become part of its developmental repertoire, modifying gene expression profiles without alterations to the underlying DNA sequences. Epigenetic states can be maintained through mitoses but also through meioses and be transmitted from one generation to the next. In the animal kingdom, examples of epigenetic events transmitted from one generation to the next are rare [4]. In rats [5] or mice [6], nutrition has been shown to affect the phenotype of the offspring. Variability in the mouse Agouti phenotype (itself related to obesity and predisposition to diabetes) [7] has been reported in a homogeneous genetic background. A few examples of epigenetic inheritance in humans are still under debate such as grandchild phenotype which would depend on grandmother’s or grandfathers food supply or smoking [8]. On the contrary several responses to environmental conditions such as nutrition or stress at early stages of life resulting in different phenotypes during adulthood have been reported. Animal cloning clearly established a maternal imprinting during fetal life which affects growth and health in adults. In humans, it has been shown that mothers exposed to starvation during pregnancy give birth to children who will be on average smaller as adults [9]. When exposed to endocrine disruptors, women will give birth to males which will exhibit severe sexual disorders [10]. After birth, during the first week of postnatal life, maternal care also influences neuroendocrine and behavioral stress responses throughout life [11]. The most spectacular example might be the different phenotypes of “Queen” or “worker” observed in honey bees, depending on the nutrition of the larvae [12]. Thus epigenetics can explain the phenotypic outcome of interactions between environment and genetics, but it can also be seen as the basis of cellular differentiation. In that sense, it explains that in a multi-cellular organism development generates a plethora of cell types with distinct functions and diverse but stable gene expression profiles despite the shared genotype (same DNA) of the cells. E. Devinoy (*) INRA, UR1196, Genomique et Physiologie de la Lactation, 78 352 Jouy en josas Cedex, France e-mail: eve.devinoy@jouy.inra.fr

Lineage-dependent mating-type transposition in fission and budding yeast

The basis of cellular differentiation is perhaps best understood in the yeast mating-type switching system. The yeast cell produces daughter cells that differ from each other or from their parent cell via developmentally regulated genomic rearrangements. Recent experiments on cell-type determination in fission yeast have revealed that this process is determined by the inheritance of specific parental chromosome strands by the progeny cells.

Mucoepidermoid carcinoma of the larynx. A clinicopathological study of 11 cases with review of the literature.

A series of 11 cases of mucoepidermoid carcinoma of the larynx is presented. The neoplasm is uncommon and the present series has been selected from 872 primary malignant neoplasms of the larynx evaluated at the Section of Pathology of ENT Department of Padua University from January 1975 to December 1979. The median age of the patients was 59 years. The most common location was the epiglottis. The tumors were classified on the basis of cellular differentiation, and common and/or uncommon pathologic features were recorded. Differential diagnosis must be made from several neoplasms, in particular from squamous cell carcinoma, adenoid cystic carcinoma and adenosquamous carcinoma. The treatment of choice is surgery. The prognosis is better than that of the commoner squamous carcinoma and depends both upon the stage and the histologic grading.

Liposarcoma of the Extremities and Limb Girdles

A study was made of 222 cases of liposarcoma of the somatic soft tissues of the extremities and limb girdles. The male-to-female ratio was 1.6 to 1. The mean age of the patients when they were seen at the Mayo Clinic was 50.2 years—the youngest patient was nine years old and the oldest eighty-one. The lower extremity was involved three times more often than the upper, and the proximal portions of the limbs were affected more often than were the distal. Roentgenograms, available for review in sixty-six patients, revealed the presence of a soft-tissue mass in thirty-nine. Twenty-eight tumors were more radiopaque and eleven less opaque than the adjacent soft tissues. Ten of these thirty-nine tumors demonstrated areas of both increased and decreased opacity. Liposarcomata present a varied but coherent spectrum of histological appearance. The tumors may be divided by their gross and microscopic appearance into three types: myxoid, lipogenic, and pleomorphic. Histological examination substantiates and refines this classification on the basis of cellular differentiation. In our patients, 46.4 per cent of the tumors were myxoid, 20.3 per cent lipogenic, and 33.3 per cent pleomorphic. The differentiation of the malignant lipoblasts in each type of liposarcoma was expressed numerically (grade 1 through 4): 23.0 per cent were grade 1; 26.6 per cent, grade 2; 39.2 per cent, grade 3; and 11.3 per cent, grade 4. The grade and type of malignancy remained constant with each recurrence of tumor—except in the case of one grade 1 myxoid type tumor. Metastasis occurred only three times when the lesions were grade 1—twice when the lesion was of the myxoid type and once when the tumor was of the lipogenic type. Recurrence of this tumor is extremely common and strongly influences the treatment and prognosis. Of patients treated by local excision and observed for five years or more, 70.4 per cent showed evidence of recurrence. Initial treatment consisted in irradiation in two patients, local excision in 196, and primary amputation in twenty-four; subsequently, after one or more local recurrences, forty-two of the 196 patients treated by local excision required amputation. Nineteen patients had a successful initial excision, but 138 patients experienced one or more local recurrences. After primary amputation, fifteen patients were alive (six less than five years), eight were dead, and one was lost to follow-up at the time of writing. Of the patients undergoing amputation after one or more local recurrences, nineteen were alive (three less than five years), twenty were dead, and three were lost to follow-up. Ten patients received roentgen treatment for primary or recurrent tumor. None of these exhibited any demonstrable effect, and each died of his tumor. The five-year survival rates, according to the type of tumor, were as follows: lipogenic, 60.0 per cent; myxoid, 47.3 per cent; and pleomorphic, 33.3 per cent. According to the grade of differentiation, the rates were as follows: grade 1, 75.0 per cent; grade 2, 40.0 per cent; grade 3, 37.3 per cent; and grade 4, 31.8 per cent. The five-year survival rate in 166 determinate cases was 44.6 per cent. The ten-year survival rate was 22.8 per cent. The rather substantial loss of patients as the result of this tumor (53.4 per cent of those observed for the first five years and 19.2 per cent of those observed during the second five-year period), the high recurrence rate after local excision (70.4 per cent), and the propensity of the higher grade of tumors to metastasize even after long latent periods, all indicate that liposarcoma is a deceptive and dangerous tumor.

A Hierarchy of Self-Limiting Reactions as the Basis of Cellular Differentiation and Growth Control

An hypothesis of cellular differentiation based upon the differentiation of cytoplasmic particles similar to tumor agents and differentiating like the surface antigen system in Paramecia as demonstrated by Sonneborn is suggested. Various facts are assembled and used as the basis for a suggested mechanism of pattern formation. Differentiation as it proceeds from a center of organization, seems to occur not as the result of release of a series of specific inductors, but by the release of a general stimulus upon which is superimposed a series of specific inhibitions. One universal characteristic of differentiating systems is a progressive loss of potency. The loss increases with time and with distance from a center of organization. The center is characterized by higher general metabolism than any other qualitatively similar locus, and is the first region to do certain things. Once an organization center has become active, other less rapidly developing regions are inhibited and do not attain the high level of differentiation proceeding in the center. It is suggested that differentiation consists of the successive inhibition of one gene-initiated reaction after another by the collection of specific metabolites which inhibit in the mass-action relationship. A major assumption in the hypothesis is that there are specific metabolites which in sufficient concentration will inhibit differentiation of the cell type which produced them. An initial test seems to support this view. Bloodless, heartless and nerveless tadpoles have been produced by culturing embryos with either living adult blood cells, or pieces of heart or pieces of brain in the medium.