Friday, January 7, 2011

My thoughts on cancer biology

Cancer is a global challenge. An overwhelming amount of scientific, medical, and social progress has been achieved in the last 30 years with respect to cancer. However, cancer remains a vexing economic, health, and community challenge around the world. It is estimated that 1,529,560 Americans (789,620 men and 739,940 women) will be diagnosed with and 569,490 men and women will die of cancer of all sites in 2010.(1) Indeed, the lifetime risk of being faced with a cancer diagnosis is ~1 out of 2 for every man and women, i.e. 40.77% of men and women born today will be diagnosed with cancer of all sites at some time during their lifetime. On January 1, 2007 there were 11,713,736 living US citizens, 5,353,054 men and 6,360,682 women, who had a history of cancer of any site.1 Globally, the statistics are staggering. It is estimated that 12.9 million new cancer cases were diagnosed in 2009 and this number is expected to rise to 16.8 million by 2020.(3) It is the second leading cause of death and disability both in the US and worldwide.
The global burden of cancer, based on the incidence of new cases and deaths, has doubled within the last 30 years.2 The costs associated with this burden include medical spending such as costs of diagnosis, in-patient treatment and care, and out-patient treatment, in addition to productivity losses such as lost income due to cancer morbidity associated with new cancer cases. The worldwide cancer costs, excluding research expenditures have been estimated to be at least $286 billion in 2009 alone.(3) That sum does not include the topic of this document; the amount spent on cancer research, which totals at least $19 billion worldwide.(3) Lastly, it should be emphasized that although the disease is indiscriminate with respect to socio-economic boundaries, the global funding for cancer research is almost entirely accounted for by developed nations.

The infrastructure of the scientific and research communities of the US and the personel have contributed immensely to our current understanding of cancer biology.

This post will follow an outline format to provide an overview of the following:
I. Our understanding of cancer biology in 2010
II. Major accomplishments of academic, biotechnology, and pharmaceutical research on cancer
III. Remaining problems for scientists and physicians working in cancer biology
IV. Specific areas of high priority research
V. Concluding remarks and overall progress report

I . Cancer is the common term for all malignant tumors. There are >100 types of cancer, each classified according to the types of cells from which they develop. We understand cancer to be an abnormal mass of tissue, compromised of cells, the growth of which exceeds and is uncoordinated with that of the normal tissues.4 Most affect solid tissues, but some such as leukemias and lymphomas can be distributed throughout the circulatory system.
The mechanism of disease is incredibly complex and not fully understood. The growth of cancers is often described as occurring without restraint because of, when left to their own natural history, the ability to colonize and invade foreign tissues. This persistence of growth and inability to undergo normal processes of restraint results from somatic genes (although occasional germline mutations are present) inside the tumor cells that are heritable elements passed down to the progeny of the tumor cells. Often, the genes of tumor cells are in fact the driving force that allows for autonomous, excessive, and unregulated growth. Despite the knowledge that cancer is a genetic disease, we also know that only a minority of cancer syndromes are heritable.
Fundamental to cancer biology is the notion that the entire population of cells forming a tumor arises from a microevolutionary process whereby a single cell experiences an initial insult, often genetic damage acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or inherited in the germ line. This damage leads to dysregulation of the cellular machinery controlling replication, the integrity or fidelity of the genomes, adherence to surrounding cells, and the biochemical/physical communication with the organism at large. This event is termed transformation.(5, 6)

The progeny of the transformed cell has the same or similar alterations and therefore are known to be clonal.11 As tumors grow, local invasion of a tissue can occur. In a process that is now understood to be multi-step, as time passes (depending on the context the scale ranges from days to up to years or decades), tumor progression occurs where further alterations and mutations accumulate and may lead to the ability of some cells within the tumor to enter into the circulatory system and eventually invade distant areas of the body, i.e. metastasize. This process is the subject of intense scientific scrutiny. And there is substantial evidence to support that there are steps leading to the phenomena of metastasis and that these steps reflect accumulating genetic alterations.7, 8, 9, 10 In other words, the temporal progression of a cell from a normal differentiated epithelial cell to a life threatening carcinoma requires multiple and successive mutations and/or alterations working under the selective pressures of a permissive microenvironment, each of which conferring growth advantage and laying the foundation for metastatic potential.16
Metastatic cancer represents the major cause of cancer-related morbidity and mortality. Metastatic disease can be thought of as monoclonal, because at any point in time, one sick cell gave rise to all subsequent cells, in addition to being heterogeneous, because progeny cells can undergo further alterations. This is to say that cancer is a disease with dynamic changes to its genome and behavior, and that each case of cancer is characterized by its own array of genetic lesions, e.g. recently completed genome-wide sequencing analysis of breast and colon cancers has revealed that individual tumors accumulate an average of 90 mutant genes.10
To summarize the above, the behavior of malignant tumors can be divided into four phases: (1) transformation; (2) local growth; (3) local invasion; and (4) distant metastases. Each of these phases is now better understood because of rigorous study in multiple fields of scientific inquiry at the level of molecular mechanisms. This growing understanding holds incredible promise for the future in reducing disease burden and mortality from cancer because the scientific body of knowledge is the source upon which medical advances are drawn. Indeed, the rational design of drugs and treatment of cancer at all levels, including diagnosis, surgery, chemotherapy, radiation, recovery, and remission demands an understanding of the properties that cancer cells acquire as they grow, evolve, and spread.

II. The major accomplishments in cancer research include the discovery of the critical genes involved in cancer and the development of effective treatment strategies for some patients with metastatic disease. Both of these broad categories of advancement were made possible by the inquiry into the molecular basis of cancer cell behavior, i.e. cellular and molecular biology and the tools that those fields of study have developed. The technologic progress accomplished in these fields is massive. To name a few; we can now amplify, copy, and read gene sequences in a matter of hours with incredible fidelity; We can query proteins expressed by cells accurately and with confidence; Cells can be sorted on the basis of specific expression markers; human cell lines can be used to test drug efficacy; and many other revolutionary technologies. Through the techniques of molecular biology, in the 1970s, scientists became aware of two families of genes that are predominately involved in transformation:
(1) Oncogenes, which are genes involved in growth and when mutated or altered cause normal cells to proliferate. No single oncogene can fully transform cells in vitro, but cells can be transformed by combinations of oncogenes. Such cooperation is required because each oncogene is specialized to induce part of the phenotype necessary for full transformation.7
(2) Tumor suppressor genes, which are regulatory elements within cells to oversee and coordinate cell division, repair mistakes in DNA replication, and to initiate programmed cell death or apoptosis if needed. We now know that the emergence of malignant tumors requires mutational loss of many genes, including those that regulate apoptosis and senescence.8
We also now know DNA repair genes can be mutated but do not directly transform cells by affecting proliferation or apoptosis. Instead, they affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes.14, 15 Additionally, a new class of regulatory molecules, called microRNAs has recently been discovered. Although they do not encode proteins, different families have been shown to act as either oncogenes or tumor suppressors.12, 13
Another area of accomplishment, made possible by cell cultures is the discovery that mutations that cause cancer are often induced by carcinogens acting as mutagens. The mechanism can vary from viral insertional mutagenesis (about 1/5 of the worlds cancers are caused by viruses), to carcinogenic chemicals causing DNA adducts, and ionizing radiation acting to induce breaks in DNA strands.
The model that has been produced from research proposes a set of rules, including 6 hallmarks listed below, helping us understand how cancer cells differ from normal. This knowledge can lead to targeting therapies, such as the development of Gleevec to treat the specific oncogenic event in chronic myelogenous leukemia.17 These physiologic changes of cancer cells include:6, 9
• Self-sufficient growth signals or constitutively activated growth factor signaling.7, 9, 18, 19
• Resistance to anti-growth signals or inactivated cell cycle checkpoint20, 21
• Immortality or limitless replicative potential22, 23
• Resistance to cell death via activated anti-cell death signaling24, 25, 26
• Sustained angiogenesis via activated VEGF signalling27, 28
• Tissue invasion and metastasis by multiple mechanisms including loss of cell-to-cell interactions29

III. The principles above provide a foundation of strength in moving forward and working on cures for various cancers. However, a major challenge stems from the diversity of the >100 cancers known and because of this diversity, progress in the clinic has been slow. Although there are unifying principles, there will almost certainly never be a single cure. The spectrum of cellular pathophysiology is too broad. Moreover, as living cells with remarkable growth advantage, the microevolutionary process creates a difficult problem, e.g. a patient with breast cancer can have their original tumor tested for a specific oncogenic aberration and can be found to be negative in their primary tumor but positive in a distant metastasis. The current targeted drug for this mutation is also known to make the disease worse in people who lack the mutation, so what should be done in that scenario? It is also known that tumors can become treatment resistant and that even some of the new targeted agents such as VEGF inhibitors, over time, select for even more aggressive disease.
Cancer is indeed a terrible disease and although there have been successes with hematologic malignancies (especially amongst children) and germ cell tumors, many carcinomas are still very difficult to treat. The oncology literature generally proclaims statistical victories with P<.05 despite only weeks of survival gains. Indeed, it has been said that the clinical research efficacy bar is currently set too low, therefore hindering progress and that the “objectives, methods, and regulation of clinical trials need to change so that we can rapidly move drugs from the lab into the clinic, and then define those drugs that are effective and those patients who are most likely to benefit”.30
IV. Future areas of research ought to lead to substantial improvements in patient care and be conducted with that purpose in mind. Although many unanswered biological questions remain and represent missing links in a comprehensive understanding, with limited funding, the eventual contribution to patient care should at least be considered in deciding which questions to pursue. Promising areas include:
• Using viruses to treat cancer
• Gene therapy
• Helping the bodies immune system destroy cancer cells
• Designing drugs that target malignant cells
• Starving tumors of their blood supply and taking advantage of cancers’ altered metabolism
• Improving diagnostic tests
• Improving/reducing costs of care
• Helping the developing world with their cancer burden

V. Despite the complexities involved in understanding cancer, there is a concept amongst the experts of the cancer biology community, that cancer research is a logical science, “where the complexities of the disease, described in the laboratory and clinic, will become understandable in terms of a small number of underlying principles”.6 There is a notion that various aspects of tumor biology, although diverse and complex in scope, are supported in the literature to be “acquired capabilities-shared by most and perhaps all types of human cancer”.6 This guiding principle is the conclusion drawn from the observations made by the field of cellular biology and indeed fundamental to biology itself, that virtually all mammalian cells share similar processes and machinery which regulates proliferation, death, and differentiation.6

Figure references:
Table page 1- Reference #3
Figure 1, 2, 3- Reference #5
Table page 5- Reference #30

Text References:
1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, based on November 2009 SEER data submission, posted to the SEER web site, 2010.
2. Boyle P, Levin B (eds.) World Cancer Report 2008, Lyon: International Agency for Research on Cancer. 2008.
3. The Economist. “Breakaway: The Global Burden of Cancer-challenges and opportunities”, a report from the Economist Intelligence Unit 2009. Sponsored by LiveStrong.
4. Willis R: The Spread of Tumors in the Human Body, London, Butterworth, 1952.
5. Kumar et al. Robbins Pathological basis of Disease. 7th Edition. Elsevier Saunders
6. Weinberg RA, Hanahan D: The hallmarks of cancer. Cell 2000; 100:57.
7. Halazonetis TD, et al: An oncogene-induced DNA damage model for cancer. Science 2008; 319:1352.
8. Knudson A: Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157.
9. Hahn W, Weinberg R: Rules for making human tumor cells. N Engl J Med 2002; 347:1593.
10. Wood LD, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007; 318(5853):1108.
11. Gale RE: Evaluation of clonality in myeloid stem-cell disorders. Semin Hematol 1999; 36:361.
12. Zhang W, et al: MicroRNAs in tumorigenesis: a primer. Am J Pathol 2007; 171:728
13. Rana TM: Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8:23.
14. Jiricny J, Marra G: DNA repair defects in colon cancer. Curr Opin Genet Dev 2003; 13:61.
15. Friedberg EC: How nucleotide excision repair protects against cancer. Nat Rev Cancer 2001; 1:22.
16. Loeb LA, et al: Multiple mutations and cancer. Proc Natl Acad Sci U S A 2003; 100:776.
17. Kurzrock R, et al: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003; 138:819.
18. Sharma SV, Settleman J: Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes and Development 2007; 21:3214.
19. Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17:45.
20. Kastan MB, Bartek J: Cell cycle checkpoints and cancer. Nature 2004; 432:316.
21. Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2002; 2:103.
22. Deng Y, et al: Telomere dysfunction and tumor suppression: the senescence connection. Nature Rev. Cancer 2008; 8:450.
23. Sharpless N, DePinho R: Telomeres, stem cells, senescence, and cancer. J Clin Invest 2004; 113:160.
24. Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell 2004; 116:205.
25. Korsmeyer SJ: Programmed cell death and the regulation of homeostasis. Harvey Lect 1999; 95:21.
26. Igney FH, Krammer PH: Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2:277.
27. Nagy J, et al: VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2007; 2:251.
28. Bergers G, Benjamin L: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401.
29. Fidler IJ: The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nat Rev Cancer 2003; 3:453.
30. Stewart DJ, Kurzrock R.Cancer: The Road to Amiens. J Clin Oncol. 2009 Jan 20;27(3):328-33.


Lucas Miller said...

Wow--another well-written article. More of this stuff, Dan! Your unique perspective can be highly helpful to families dealing with cancer, I think.

On a purely editorial/design note, I find it hard to read long pieces in white text on black. That may be a quirk of mine and not the majority but it's worth contemplating. I may just cut and paste into Word next time...

Andy said...