The Cancer Cells That Leave Home Have Extra DNA Capabilities
by George L Gabor Miklos PhD and Phillip John Baird MD PhD
The cells that leave the primary tumor have different DNA characteristics to those that remain. It is their altered properties that enable these emigrants to leave in the first place and for their descendants to infiltrate and destroy vital organs. (20, 21, 22, 30, 31)
All normal cells have two copies of their DNA, one set from the mother and one set from the father. There are thus two DNA code books (instructions-for-cell-survival) in every normal cell. If one book is damaged, there is always a good copy from which to make repairs in an emergency. Normal cells carefully follow the instructions encoded in their DNA and execute them in a particular order and at specified times. Normal cells are tightly constrained by their two-book genetic operating manuals.
By contrast, cancer cells that have left the primary tumor and are in transit or have arrived at their final destinations, have massively disrupted DNA contents. Their instructions-for-cell-survival books have been copied and they have more than two of them, but with profound differences. Enormous errors have occurred during the copying process so their books now contain some extra chapters, sentences and paragraphs, while some other chapters, paragraphs and sentences have been completely deleted. Furthermore, differing amounts of text have been shifted from one place to another and at the most basic level, single letters have been changed. These single letter changes are commonly referred to as mutations (6,32).
The extent of these massive alterations in DNA is aptly described by Dr Garth Anderson, of the Roswell Park Cancer Institute in Buffalo, NY; "in most adult solid tumors the genome is shot to hell by the time the tumor is found..." and ...a mutation will not be in every cell in the tumor." (33)
The danger lies in the diversity within a cancer cell population
The mistake-prone process of DNA copying, cutting and pasting that goes on in cancer cells produces remarkable outcomes. Cancer cells no longer have to obey instructions. They have been liberated from the rigidity of conventional two-book genetic operating manuals. The ongoing process of massive alterations in DNA provides a cancer cell population with novel instructions on how to cope with various emergencies. Thus when chemotherapeutic drugs are encountered, some cancer cells in the population have different ways of dealing with drugs. No matter what defenses the body may deploy, some cancer cells in a population always have a new combination of instructions ready to face a crisis.
The cancer cells that leave home have increased informational diversity
The cancer cells that leave a primary tumor are often first found in the nearest lymph node draining the tumor and later in more distant places such as the bone marrow. A comparison of the DNA contents of individual cancer cells from the lymph nodes and bone marrow of the same patient to those of individual cells in the primary tumor reveals that cancer cells at these different locations have accumulated their own specific changes in their DNA contents. (22)
The cancer cells that leave the primary tumor represent a diverse population upon which selection will act. Some cancer cells are destroyed by the immune system, others reach the lymph nodes and progress no further, whereas still others reach an organ but are held in check by the local resident cell population and cannot proliferate. Finally, some cancer cells survive all these hazards, grow at their new sites and ultimately destroy a vital organ. In a nutshell, this is metastatic cancer.
Most cells in a primary tumor never leave
Only a small number of the cells in a primary tumor ever develop the DNA alterations to emigrate (21,34,35). If all cells had the capacity to leave, no primary tumor would be left (21). When the cells of a primary tumor are tested both clinically and experimentally for their ability to form a new tumor, only approximately 1 in 50,000 cells has the capacity to do so (34-38). Only cells that have sufficiently altered genetic operating systems or stem cell-like properties (39-41) break free of the local constraints and depart. Normal cells always remain in their local neighborhood.
(Next up: Drug Resistance and the Return of Cancer, and, New Frontier or Yet Another Unfulfilled Promise?--Dean)
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