Monday, October 11, 2010

Overview of neoplastic development

Modern tumor biology is pre-occupied with oncogenes and tumor suppressors. For the past several decades, cancer researchers have attemptedt o understand how specific genetic alterations contribute to the malignant phenotype. Certainly, research in tumor genetics has led to great advances in our understanding of cancer.

Still, tumor genetics has not really helped us understand tumor speciation. Tumor speciation is an area that gets very little attention from most cancer researchers, but if you don't have a grip on the general phenomenon of tumor speciation, you're not going to fully understand tumor classification, or carcinogenesis (the necessary biological steps leading to the development of cancer), or the biology of precancers (lesions that precede the development of cancer), or the class-based approach to precancer treatment.

Much of my book Neoplasms: Principles of Development and Diversity, is devoted to the subjects of tumor speciation and classification. I've also written about the phenomenon in prior blogs. Here's a discussion of tumor speciation, condensed to a few paragraphs.

Tumor genetics tells us that most of the common cancers occurring in adult humans are genetically complex, with thousands of mutations in tumor cells, and enormous genetic heterogeneity among the different cancer cells within the same tumor. Just as every human is genetically unique, so is every cancer that has ever occurred. If this is the case, why are the different types of cancers restricted to just a few hundred species of tumors (e.g., Wilms' tumor, chronic myelogenous leukemia, pheochromocytoma, hepatocellular carcinoma, malignant melanoma). The individual specimens within each tumor species look about the same under a microscope (that's how we diagnose them) and behave within somewhat predictable biologic paramaters. If cancers are genetically diverse, and if genetics is responsible for the behavior of cancers, wouldn't you expect to find a near-infinite number of tumor species?

The hypothesis developed in my book is that while cancer is caused by genes, tumors are speciated by epigenes, the non-sequence DNA changes that determine cellular differentiation in normal cells. Just as normal cells of the human body are restricted to a few hundred differentiated cell types [by the epigenome], cancer cells are restricted to a finite number of cell types [by the epigenome].

During carcinogeneis, cumulative genetic changes occur, but these changes must somehow fit into an epigenomic pattern that supports the continued growth of the tumor. In short, carcinogenesis is a genetic phenomenon, but tumor speciation is an epigenetic phenomenon.

Precancers are a late-stage epigenomic adjustment. If the adjustment is successful, from the perspective of the cancer cell, the precancer can develop into a cancer of a specific tumor species. Otherwise, the precancer regresses [spontaneously dies]. Precancers can be thought of as biological experiments conducted by cells undergoing carcinogenesis. Sometimes the experiment fails (and the precancer regresses). You're never sure of the result of the experiment (i.e., a precancer may develop into any one of several different tumor species, as in the case of bronchogenic precancers).

I admit that this all seems vague, but that's what happens when you try to cover a complex subject in a few paragraphs, without the aid of examples.

In the next blog, I'll introduce malignant rhabdoid tumors, and I'll try to explain how this unique tumor provides perspective to the whole problem of speciation.

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-© 2010 Jules J. Berman

key words: cancer, neoplasia, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, pre-cancer, precancerous lesions, pre-malignant lesions, neoplastic development