From Speculations to Reality and Beyond Some Implications of a Darwinian View of Cancer Progression

The confirmation of Nowell's model came from the discovery that the acquisition of the resistance of cancer cells to chemotherapy was similar to other well-known evolutionary phenomena described in medical therapy. In 1978, Robert Schimke discovered a genetic mechanism that provides the condition for a selection of cancer cells resistant to methotrexate (MTX). He showed that resistance of mouse cells to MTXresults from a selection of cells of higher contents of a specific enzyme, due to an increase in the number of copies of the gene coding for this enzyme, that to gene amplification. "The properties of the resistance of cultured cells to MTX, including (i) a stepwise selection of progressively resistant cells; (ii) an increase in a specific protein present at low levels in sensitive cells, which, when present in larger amounts, results in resistance; and (iii) stable and unstable resistance in the absence of selection pressure, have analogies both in antibiotic and insecticide resistance" (Schimke 1978; 1055).

During the 1980s the concepts of genetic instability and clonal evolution were confirmed, and the possibility that epigenetic mechanisms could exert differential selection pressures on heterogeneous cancer cell populations widely discussed. In 1986 Barry Wolman suggested that genetic and chromosomal instability was the potential source of genetic heterogeneity in all tumors, and that variation in local environmental selective pressures and differential survival may contribute to cellular heterogeneity within an expanding tumor. In turn, heterogeneity itself might permit selection and increase in number of aberrant cells which are responsible for tumor progression and metastasis. Genic and chromosomal instability are potential sources for genetic diversity within all tumors. However, variations in local selective forces and differential survival within an expanding solid lesion may contribute to maintenance of a mixed cell population within the primary tumor (Wolman 1986).

Finally, Fearon and Vogelstein (1990) proposed the now historic model of successive genetic changes leading to genetic instability producing colorectal cancer (CRC), in which a number of genes are involved, including APC, k-Ras, DCC, and p53. With few modifications, the Vogelstein model still stands and knowledge on the function and interactions of the key molecules involved, which has been obtained since it was proposed more than 15 years ago, even strengthens the genetic cascade of events in the sequence originally proposed (Weinberg 2006).

According to Vogelstein's group "the genetic instability hypothesis can be viewed as a pessimistic one," as cancer cell heterogeneity should allow the tumors to face therapeutic challenges. However, they think that instability itself could be the Achille's heel, providing a target for drugs killing unstable cells better than normal as it has been demonstrated in the case of yeast cells (Cahill, Kinzler, Vogelstein and Lengauer 1999).

Nowell was the first to put forward that the evolutionary model of cancer progression might induce a pessimistic view about the prospective of a definitive therapeutic success. If the cells within a tumor are so heterogeneous and ready to form variants in the face of therapeutic challenges, do we have a realistic chance of ever curing advanced cancer? According to Nowell (1976) "the fact that most human malignancies are aneuploid and individual in the cytogenetic alterations is somewhat discouraging with respect to the therapeutic considerations" (p. 27). Such a fact explained the failure to discover metabolic alterations sufficient to allow specific chemotherapy. "The same capacity for variation and selection, which permitted the evolution of a malignant population from the original aberrant cell, also provides the opportunity for the tumor to adapt successfully to the inimical environment of therapy, to the detriment of the patient" (p. 27).

Nowell pointed out a further consequence of the clonal evolution model of cancer, that is that each advanced malignancy has individual therapeutic problems, a view that has become adopted by the strategies aimed at developing tailored/personalized therapies (Hasegawa, Ando, Ando, Hashimoto, Imaizumi and Shimokata 2006).

A further implication of a Darwinian model has to do with the fact that any adaptive evolution is, by definition, context dependent. Anderson (2001) thinks that genomic instability should suggest that "instead of directly attacking the heterogeneous population of genomically unstable tumor cells, the invariant, genomically stable cells of the tumor vasculature become an especially appealing target." The idea role of environment was emphasized by Folkman, who saw that solid tumors are angiogenesis-dependent. That brought to the idea of fighting cancer by subtracting blood supply. These ideas have been developed in several lines, one of which brought to the invention of bevacizumab (Ferrara, Hillant, Gerber and Novotny 2004).

Nowell (1976) interpreted the concept of context dependence of cancer in terms of "potential reversibility of the neoplastic process." If the genetically unstable, highly individual malignancy is difficult to eradicate therapeutically, what is the likelihood of producing a "cure" by providing an environment which forces the tumo-r cell population to cease unlimited proliferation and move into a state of controlled differentiation?

Nowell quoted the experiment reported in 1975 by Beatrice Mintz and Karl Illmensee, who injected teratocarcinoma cells taken from embryoid bodies in vivo into developing mouse blastocysts, and obtained normal mice with no evidence of tumors. They, however, found that tumor-derived cells were present in large numbers and contributed to several unrelated tissues. Mintz and Illmensee (1975) concluded that tumor cells were developmentally totipotent and could revert to normal behavior in the appropriate environment. In 1997 Mina Bissel has shown that blocking integrin function was sufficient to revert the malignant phenotype of human breast cancer both in culture and in vivo (Bissel 1997).

More recently, Rudolph Jaenisch and his group demonstrated by using nuclear transplantation that an oocyte's microenvironment can re-establish development pluripotency of malignant cancer cells. The nuclei of murine leukemia, lymphoma and breast cancer cells can support normal preimplantation development to the blastocyst stage, but fail to produce embryonic stem cells. A blastocyst cloned from a RAS-inducible melanoma nucleus develops into ES cells with the potential to differentiate into multiple types in vivo. These findings are in some way paradigmatic for studying the tumorigenic effect of a given cancer genome in the context of the whole animal, and demonstrate that "the malignant phenotype of at least some cancer cells can be reversed to a pluripotent state despite the presence of irreversible genetic alterations and allow apparently normal differentiation. It is now important to define the epigenetic factors that influence the malignant pheno-type to help establish therapeutic strategies for cancer patients" (Hochedlinger, Blelloch, Brennan, Yamada, Kim, Chin and Jaenisch 2004).

In the light of this theoretical perspective it would be wise to overtly recognize that there will not be "the cure" of cancer, as cancer is not a single disease. There certainly will be many small successes that will steadily reduce the overall death rates from various types of cancer, including the invention of strategies that will exploit body's inherent capacity to prevent the growth of the in situ tumors naturally developing along organisms' lifetimes (Folkman and Kalluri 2004).

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