Chapter 37 / Future Perspectives 651
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Future Perspectives
Vincent J. Hearing and Stanley P. L. Leong
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Cancers arise from their normal cellular counterparts, and, in this regard, malignant melanoma is no exception. Within this book, we have traced the origins of melanoblast precursors, their differentiation to melanocytes, the regulation of their physiological functions, and the pathways by which they become malignant and eventually metasta- size. We are grateful to all authors who have made this book the first of its kind to trace the biology of melanocytes and their subsequent development to melanoma, and which details the current state of knowledge of mechanisms that underlie those processes.
Melanoma is a highly aggressive cancer and with even small increments in Breslow thickness (measured in millimeters), the clinical behavior of the tumor rapidly worsens from a relatively curable disease to a highly aggressive and fatal disease. In contrast, breast and colon cancers develop more aggressive behaviors only with significantly higher tumor burden, for example, a T2 lesion is 2 cm in breast cancer, and, often, several centimeters are noted in primary colon cancers before they become overtly aggressive.
Based on relatively small size increments, slight changes in cell volume can substantially affect the clinical behavior of melanoma.
In most instances (>95% of cases), melanoma is represented by a cutaneous distribu- tion and, therefore, careful surveillance and awareness of any atypical lesions on the skin will allow clinicians to identify earlier stages of lesions to prevent progression or advancement of melanoma to a more aggressive stage. A very challenging question is why the white population is most affected by melanoma. Does this result from intrinsic genetic differences between different racial groups that are reflected by different levels of pigmentation that might explain the different incidences of melanoma in different racial populations? If that is the case, what are the genes responsible for such differ- ences? The nagging question of whether melanoma forms as a result of the effects of ultraviolet radiation on melanocytes also needs further investigation. If that is the case, are melanocytes from the white population more vulnerable to such processes of carcino- genesis? Perhaps epidemiological studies can answer the question of whether white populations living in northern Europe with relatively lower levels of sun exposure will have lower incidences of melanoma than whites who have migrated to areas with higher exposure to ultraviolet radiation (1). The role of ultraviolet radiation in the carcinogen- esis of melanoma also needs to be further defined. Although multiple melanomas may
From: From Melanocytes to Melanoma: The Progression to Malignancy Edited by: V. J. Hearing and S. P. L. Leong © Humana Press Inc., Totowa, NJ
652 From Melanocytes to Melanoma
occasionally occur in an individual, the majority of patients present with only one site of melanoma. The obvious question that arises is why a certain site gives rise to mela- noma, whereas other sites in the same patient remain undisturbed. It is known that anatomical sites influence the outcome of a patient, for example head and neck melano- mas appear to be more aggressive (2). Is the distribution of melanomas in the head/neck or in the extremities/trunk a random or nonrandom process?
The chapters in this book detail the current state of our knowledge about biochemical and molecular events that occur in melanocytes and in melanoma cells, the stepwise progression in the transformation of melanocytes to malignant melanoma, and eventu- ally in the metastasis of the tumor (see Fig. 1 in Chapters 10 and 15 for schematics of this sequence). However, there are still many gaps in our understanding of these complex processes. The challenges for future studies will be to define the precise molecular mechanisms involved in each step. Once such mechanisms are understood, potential approaches and therapies can be devised, either to divert or halt such progression and/
or to prevent the subsequent progression of the tumor to its more aggressive form.
The issue of lymphatic metastasis through lymphatic channels vs systemic dissemi- nation through vascular channels also needs to be further explored. Are the two different modes of metastasis a reflection of the intrinsic biology of melanoma? Can it be that certain melanomas with specific molecular features will initially spread through lym- phatic channels to sentinel lymph nodes and then later disseminate through the vascular system, as in the incubator hypothesis? On the other hand, do molecular markers exist that can define melanoma cells at primary sites that will disseminate through the vascular system simultaneously, as in the marker hypothesis (see Chapter 23)? Are these two processes clonally or epigenetically determined?
This book has summarized the latest findings in the development and differentiation of melanocytes and their progression to malignant melanoma. It is clear that we are still faced with a number of important but unanswered questions that should be resolved in the years to come, which should lead to a better understanding of the mechanisms involved in the progression from normal melanocytes to malignant melanoma. The ultimate goal is not only to study the basic biology of such progression but also, hope- fully, when the mechanisms involved have been elucidated, to develop strategies for the precise and effective clinical diagnosis and treatment of malignant melanoma. It is also our hope that clinicians will soon be able to test new hypotheses developed in research laboratories and to then report those clinical observations to basic research scientists, which will allow further characterization of mechanisms involved in the transformation of melanocytes to melanoma.
REFERENCES
1. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 1999;340:1341–1348.
2. Balch CM, Soong S-J, Shaw HM. An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Sober AJ, Soong S-J, eds. Cutaneous Melanoma. J. B.
Lippincott, Philadelphia, PA: 1992, p. 165.
