Neoplastic Stem Cells
One century ago there was already the intuition that originally tumor has got cells with special features. Stem cells are reserve components of our tissues, cells that are activated only under normal circumstances to restore damage or replacement of the normal tissues. They are capable of self renewal, multi-powerful, immortal, very resistant to chemical and physical characteristics possessed also by cancer cells. They are cells that acquire properties due to the atypical nature of their genetic heritage.
With this discovery is becoming increasingly clear that the malignancy of tumors is due to the presence of mutated stem cells, that is no longer able to differentiate themselves and to normalize the physiological normal stem cells.
In life there are differentiating factors that block the cell cycle in the altered cells, which are responsible for repairing the damage of malignant cells and normalizing, or if mutations underlying malignancy are too great, pushing the cells to die spontaneously. When we get sick with cancer we are no longer able to produce factors of the normalization of altered stem cells, which multiply indefinitely.
Much has been discovered about how cancer cells multiply, little or nothing about how cancer stem cells multiply. These cells, although very few inside tumors, are those responsible for the growth of the disease and its spread in the body (metastasis). If we want to stop the growth of a tumor so we have to learn to recognize and attack the stem cells. Normally, stem cells divide in an “asymmetric”, but cancer cells, at least since we have seen, are divided in a “symmetrical”.
When a normal stem cell duplicates itself, gives rise to two cells different with each other (asymmetric division), one remains a stem, and the other specializes and gives rise to all cells of that tissue. In this way the number of stem cells remains constant and the tissue is regenerated. In contrast, stem cells in cancer is doubling in a symmetric way, each giving rise to two stem cells capable of forming tumor tissue. In this way the number of stem cells gradually increases and the cancer spreads in the body.
Even the normal stem cells can replicate in a symmetric way: when they repair a degenerated tissue. In the body there is a gene (p53) that is responsible for coordinating the process of asymmetric division. If stem cells lacking p53 lose this statement and divide symmetrically. The p53 gene is missing in about 90% of tumors. It has been shown that pharmacological reactivation of p53 correlates with restoration of the asymmetric division of stem cells and tumor reduction of tumor growth without significant effects on normal growth.
The cancer stem cells could be the engine that supplies gasoline to the development of tumors, their tremendous ability to resist drugs and reappear after some time.
The tumor proliferation is aberrant and uncontrolled, but maintains a development program, even derailed.
In the study of cancer have long lived two conflicting theories. 1 – all the tumor cells are the same with the same ability to proliferate and generate another tumor, 2 – only a small percentage of tumor cells is able to fuel the growth and development of cancer stem cells. The other would be the result of the proliferation, but unable to replace them.
The first evidence for the existence of stem cells came in 1997 with leukemia: only one in a million cells of leukemia re-generated when implanted into mice. Currently stem cells have been found in solid tumors: breast, prostate, melanoma and brain. It was seen that these stem cells are partly similar to the normal. Now we start to look for surface proteins that specifically characterize them.
If stem cells are the origin of cancer, you might understand why arms used to fight it till today were not useful. When a stem cell divides to generate two cells, one retains the characteristics of stem cells to repair and remains, while retaining the characteristic of stem, the other undergoes a rapid process of proliferation and maturation but runs out quickly. It can be assumed that the bulk of the tumor consists of cells now arrived at the end of the proliferative cycle. Instead, few stem cells while remaining at rest, would be able to fuel the growth of the tumor. The trouble is that the drugs available today mainly affects cells that divide very quickly.
We must find specific molecular targets of cancer stem cells. This will give rise to very specific therapies with very different views, as currently antiblastic drugs affect cells that divide rapidly while saving much cancer stem cells that are at rest. Besides the stem cells are able to resist, and probably have mechanisms by which they can take out of the cell membrane chemotherapy drugs.
The fight is difficult but we must not keep persisting.