Understanding Cancer (Part 1)
“tumors destroy man in a unique and an appalling way, as flesh of his own flesh which is somehow rendered proliferative, rampant, predatory and ungovernable. They are the most concrete and most formidable of the human maladies, yet despite more than 70 years of experimental study they remain the least understood.”
Francis Peyton Rous; Nobel lecture, 1966.
In this series, we shall try to discern the biology and history of cancer, along with the latest developments in the field.
Origin of tumors and their classification
Interestingly, tumors were previously thought to be foreign bodies in a patient. However, the scenario is much different now, with us being able to identify and learn about the different types of cells under the microscope.
Because of these histopathological studies and comparisons, we can now conclude tumors to be cells that have lost the ability to assemble and form tissues.
Normal body cells arise from the three basic germ layers- Ectoderm, mesoderm, and endoderm. When these cells mutate, they give rise to tumors.
So Sarcomas are tumors that arise from the mesenchyme (which is undifferentiated embryonic tissue found in the mesoderm)
Carcinomas originate from the epithelial layer of tissues.
Hematopoietic tumors arise from blood forming tissues including immune cells. They are derived from the embryonic mesoderm.
The last major category is that of tumors of the central and peripheral nervous system, called neuroectodermal tumors.
However, some tumors are unruly misfits that do not classify into the above mentioned categories- Melanomas (arising from melanocytes, which in turn arise from a primitive embryonic structure termed the neural crest cells)
Another example is Small cell lung carcinoma. They contain cells have an embryonic origin from the neural crest cells similar to that of adrenal glands. A very interesting phenomenon is that because of this feature, they are able to secrete bioactive peptides. It is unclear whether SCLC, frequently seen in tobacco users, arise from neuroectodermal cells that have lodged themselves in the developing lung or whether the tumors originate in endodermal cell populations of lung that have shed some of their epithelial characters and taken neuroectodermal lineage.
The more likely alternative seems to go with the latter. The process by which this happens is said to be transdifferentiation. The term implies that a mature cell changes phenotype from one differentiation lineage to another, such a change is said to occur in both normal and cancer cells. This change in phenotype is termed epithelial-mesenchymal transition.
Monoclonality of cancer
The next big question in cancer biology was that of the clonality of cancer. Do tumor cells originate from a single ancestral cell or from a series of genetically distinct subpopulation of cells?
The answer to this was found out from lineage tracing of cells. The gene for glucose-6-phosphate dehydrogenase is located on the x chromosome and more than 30% of African American women are carrying heterozygotes at this locus. Because of X chromosome silencing in females, each of these heterozygous women will only express one or the other allele of G6PD gene. In 1965, observations were reported on a number of leiomyoma in African-American heterozygotes. Each leiomyoma expressed either one or the other variant form of G6PD enzyme. From this we can essentially conclude that cancer arises from a single founding progenitor cell.
However monoclonality of cancer has its caveats, the population of cancer cells develop genotypic and phenotypic instability of cell populations. The subpopulation of cells growing in the tumor can develop mutations and can result in genetic heterogeneity. This can lead to a polyclonal tumor. Nonetheless , it is of widespread agreement that the vast majority of advanced human tumors arise from a progenitor cells.
How do cancer cells meet their energy requirements?
The energy metabolism of cancer cells differs markedly from that of normal cells, a trait first reported in 1924 by Otto Warburg, he discovered that even in the presence of ample oxygen cancer cells rely largely on glycolysis. The fact that cancer cells metabolize glucose so inefficiently requires them to compensate by importing enormous amount of glucose. Because of this cancer express elevated levels of glucose transporters particularly GLUT 1 (Radiologist take advantage of this by injecting radiolabeled glucose). This use of glycolysis as a primary source of energy seemed inefficient as they yield comparatively less energy. The explanation to the reason why cancer cells chose aerobic glycolysis (Warburg effect) were many but the most popular one states that glycolysis serves a second role independent of ATP generation. The intermediates in glycolytic pathway function as precursors of many molecules involved in cell growth, including the biosynthesis of nucleotides and lipids. By blocking the last step of glycolysis, these glycolytic intermediates can be diverted to biosynthetically important reactions. One can assume that this is where the origin of the myth that “cutting down of sugar can cure cancer” stems from.
A complete explanation of Warburg metabolism is still not at hand but the way cancer cells mediate “aerobic glycolysis” is resolved. The enzyme for the conversion of phosphoenolpyruvate to pyruvate is catalyzed by Pyruvate Kinase, this enzyme has two isoforms M1 and M2. The M1 isoform ensures that its product, pyruvate goes from the cytosol into the mitochondria. The M2 form of the enzyme (present in early embryonic cells and cancer cells) has a very low turnover number, which results in the backup of glycolytic intermediates and their diversion into biosynthetic pathways.
We shall continue our discussion in part 2, wherein we will discuss Tumor viruses.
-Johan J and Anushka D (third year medical students )
References:
1) The Biology of Cancer by Robert Weinberg
2) Robbins and Cotran pathological basis of disease
