Consequently, “inactivation” of tumor suppressor genes must occur in order for the effect of an activated oncogene be felt. Alternatively, activation of more than one oncogene might overcome the suppressing effect of the normal tumor suppressor genes.
With scores of oncogenes having been discovered and several tumor suppressor genes having been identified, one wonders, especially after seeing no “universal” pattern related to molecular, biochemical, or cellular structure of function within or between tumor types, if a unifying hypothesis will ever explain these observations. To date, proto-oncogenes and their tumor-related counter-parts, the oncogenes, seem to code for growth factor or growth factor receptor molecules, molecules found in the cytoplasm (transmembrane signally elements needed for cell growth much as coded by the Ras oncogene) or the nucleus (transcription elements needed to regulate gene expression such as Myc)(Weinberg, 1985). The tumor suppressor genes, again, represent a completely different set of genes (Harris, 1988; Klein, 1987; Knudson, 1985; Lee et al., 1991; Sager, 1986).
While some tumor types (e.g., breast cancer) have been associated with a high frequency of particular oncogenes (Slamon et al., 1987) [or loss of specific tumor suppressor genes] (Malkin et al., 1990)), the association has never been shown to be universal. In other words, there seems to be several ways or combinations of oncogenes and tumor suppresson genes by which a given type of cell can be converted to a cancer cell.
Earlier concepts had suggested that one needed at least two oncogenes to make a normal cell a cancer cell (e.g., a Myc-type to “immortalize” a cell and a Rastype to transform it to a malignant phenotype). Then it was shown one could transform some cells with only one oncogene (Spandidos and Wilkie, 1984). Later, to make things more complicated, the loss of tumor suppressor gene function was needed (Harris, 1988; Klein, 1987; Knudson, 1985; Lee et al., 1991; Sager, 1986). In addition, others seemed to indicate that while, genetically only “two-hits” seemed to be needed for cancer-prone syndromes such as retinoblastoma (Moolgavkar and Knudson, 1981), many more “hits” were needed to transform human colon and bladder cells (Marx, 1989; Vogelstein et al., 1988). In addition, others seemed to indicate that while, genetically only “two-hits” seemed to be needed for cancer-prone syndromes such as retinoblastoma (Moolgavkar and Knudson, 1981), many more “hits” were needed to transform human colon and bladder cells (Marx, 1989; Vogelstein et al., 1988).
On one hand, these observations might simply mean that the number of changes needed to transform some cells is different than for others, it could also mean the manner in which these studies were done demand different interpretations. For example, in the case of whether one or two oncogenes are necessary to transform a normal cell, one might ask if in the case o;f one oncogene being sufficient whether those cells already had highly expressed “proto-oncogenes” or exogenous factors in the cell culture system which interacted with the assed experimental oncogene. Secondly, in the case of the multiple oncogenes needed to transform human lung epithelial or bladder cells, one needs to know if the culture conditions forced the need for multiple oncogene changes which might not be needed in vivo. Alternatively, the target cells used in these experiments might not be the “target” cells in vivo.
One additional way of conceptualizing this complex set of observations is to view, not the individual specific molecular/biochemical nature of the oncogene/tumor suppressor gene products, but their cellular net effect and its consequence on an important cellular function; namely, the maintenance of homeostasis.
The “Yin/Yang” model of oncogenes/tumor suppressor genes might be a way to explain the perplexing array of experimental observations on oncogenes/tumor suppressor genes. Moreover, as will be seen in the next section, independent of the specific oncogene/tumor suppressor gene interaction in any given tumor, if the consequent of each type of these interactions is the loss of homeostasis, then the unifying concept for all these combinations might be the answer to this questions: “What is the cellular basis for tissur homeostasis?”.
As is illustrated in Figure 4, a cell has normal growth control, and it has a specific balance dictated by the particular proto-onogene/tumor suppressor genes expressed in that particular tissur (e.g., breast, lung, liver). However, if that balance is upset by the proto-oncogenes being activated such that they can negate the normal tumor suppressor genes in that particular tissue micro-environment, the the cell would have a growth advantage. Alternatively, in another cell, this (these) activated oncogene(s) might still be controlled by the normal tumor suppressor genes in that micro-environment. If the tumor suppressor genes function is lost or suppressed by the micro-environment, then again the cell would have a growth advantage.
Since certain oncogenes might be expressed in only certain tissues or since the physiological state of different differentiated cells expressing the same oncogene is different, it would not be surprising to find that in one cell the activated oncogene is associated with transformation, yet in the other it is not. The point is oncogenes and tumor suppressor genes do not act in a vacuum. Their interaction is in the context of a complex interacting set of that interaction is not only on that cell, but on a community of interacting cells.
Integrating this concept with the “nature and nurture” concept, one finds the Li-Frameni syndrome as an example where an inherited gene, which predisposes the individual to certain types of cancer, appears to be a tumor suppressor gene (Malkin et al., 1990). In other words, at conception, these individuals inherit one mutated tumor suppressor gene. During development and life, if it acquires an activated oncogene in a stem cell of an organ in which the mutation or loss (deactivation) of the second tumor suppressor gene has occurred, then cancer would develop. Why tumors do not occur in other organs of this syndrome even though the inherited mutant tumor suppressor gene is found in all the cells is not known.
