Special Feature
Deciphering the Clues that Make Cancer...'Cancer'
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: The Cancer Genome Atlas is an ambitious collaborative project aiming to sequence the genome of cancer. The initial output has already demonstrated the extreme heterogeneity of different primary tumors, opened new avenues of therapy, and described insights into the origins of disease. Clues to the functional consequences of these molecular aberrations are coming to light providing a new understanding as to the "why" this disease behaves as it does.
Sources: Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature2011;474:609-615. Nieman KM, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med 2011;17:1498-1503.
The Cancer Genome Atlas research network (TCGA) is an open-sourced multi-institutional collaborative charged by the National Cancer Institute (NCI) and the National Human Genome Research Institute effort to explore the molecular aberrations of cancer to better understand the disease and identify new treatment approaches. Given its poor prognosis and stagnant treatment outcomes, high-grade serous ovarian cancer was one of the original three cancers to undergo systematic and comprehensive genomic characterization utilizing innovative technologies. The tumors were well annotated as to their origin, treatment history, and clinical characteristics (such as surgical cytoreduction outcome, response to therapy, and survival). From the tumor specimens, genomic and epigenomic (acquired) alterations were catalogued using high-throughput technology. The ovarian cohort included 489 samples. As appreciated previously, mutations in the housekeeping tumor suppressor gene, P53, represented nearly all tumors (96%). Low-prevalence but noteworthy somatic mutations included BRCA 1 & 2, RB1, CDK12, and NF1. Subtypes of this histology were clearly evident and impacted survival; importantly, defects in homologous recombination represented half of the cases. These classifications better help to stratify patients with the same histology into different prognostic and therapeutic cohorts. The enduring return from the TCGA project is its searchable database of the tumor genome, which provides an avenue to explore new hypotheses of this cancer's driving pathophysiology.
One nearly universal characteristic of advanced stage ovarian cancer is omental metastases. It is often the largest volume of tumor in patients when the diagnosis is made, yet there is little understanding as to why this occurs. To explore whether omental metastases are a random or a tropic event, a detailed preclinical examination was focused on the omental adipocyte. The series of in vitro and in vivo experiments demonstrated that omental adipocytes promote homing, migration, and invasion of ovarian cancer cells and that adipokines, including interleukin-8 (IL-8), mediate these activities. Omental adipocytes also act as an energy source for cancer cells by directly transferring lipids. In addition, a specific protein (fatty acid-binding protein 4, FABP4) appears to regulate this process and is activated at the tumor-adipocyte interface. Blocking FABP4 drastically impairs metastatic tumor growth, suggesting its central role in the tumor microenvironment. This novel target represents not only a key piece to the puzzle of why omental disease occurs, but also, a new therapeutic avenue with tumor selectivity and prevention potential.
Commentary
"The beginning of knowledge is the discovery of something we do not understand."
— Frank Herbert
Several years ago during a counseling session with an ovarian cancer patient and her family, a concerned sibling asked, "Is this cancer genetic?" Before I could address the nuances of "familial cancer" and tumor biology, the patient responded saying, "Sis, all cancer is genetic!" Indeed, it is really only of late that the truth of that statement is being fully appreciated.
I've taken the liberty of drawing attention to two papers that provide some of the background to which the mysteries of ovarian cancer biology are being unraveled. The first is the long-awaited initial publication from the TCGA effort. As mentioned, the NCI commissioned this colossal effort more than 5 years ago, bringing together scientists and clinicians from multiple academic centers and industry with expertise in genomic laboratory investigation, statistical methodology, tissue procurement, and disease treatment to "crack the code" of ovarian cancer. The approach was straightforward, but it required a "divide and conquer" collaborative effort. Every aspect of the multitudes of investigative technologies being employed had to be vetted and validated. The clinical annotation needed to be equally precise, because the endpoint of a binomial or continuous variable was often the discriminating factor in analysis. This became really important to pose a question such as, "What genes are differentially expressed when a tumor is resistant to chemotherapy?" Or, "What is different about patients who never recur after primary therapy as opposed to those who never responded in the first place?" The answers to these types of questions provide clues to understanding biology, and allow focused development of treatments so it is much less random.
Anticipation for the data emerging from this initial publication in the cancer world was not dissimilar to that experienced by NASA engineers awaiting first pictures of the Martian surface. A good appreciation of what they expected to see had been amassed from reconnaissance probes, but to see the detail provided by the Mars Rover brought a whole new level of understanding, and as has been the case since, new hypotheses of the planet's dynamic processes. One of the great surprises from the ovarian cancer data set, particularly as compared to glioblastoma multiforme undergoing the same analytical assessment, was the widespread instability seen in the genome. Nearly every chromosome has some gene or sets of genes that are either lost or amplified. It looks nearly random. However, in this chaos, there were four distinct "signatures" of biology (differentiated, immunoreactive, mesenchymal, and proliferative) that help to categorize different tumors, and for all intents and purposes, look identical to the eye. Analysis of survivorship among these signatures helps to explain why some patients do relatively well, and others do not, despite being similar clinicopathologically (age, grade, stage, surgery result, and chemotherapy use), and importantly, new therapeutic targets not previously known. While the lab-to-patient pathway can be somewhat long and besieged with frequent setbacks and tangents, one of the unique observations from the TCGA was the frequent observance of somatic alteration in the genes governing homologous recombination. This high-fidelity reparative pathway of DNA damage is a primary survival technique of cancer cells being attacked by certain types of chemotherapy. The knowledge that nearly half of high-grade ovarian cancers have a deficiency of this pathway indicates that the tumor cells are using other lower fidelity pathways to survive.1 One dominant pathway is PARP. Readers of OB/GYN Clinical Alert may recognize this enzyme and the class of inhibitors targeting PARP, because they have recently demonstrated single agent activity in women with recurrent disease, and prevented the recurrence of treated disease in others.2,3 It can be anticipated that the number of new treatment approaches individualized to specific tumors will be in our future as this data is more thoroughly interrogated.
The second paper, through a series of elegantly constructed experiments, helps to explain the mechanism behind a feature of ovarian cancer well known to anyone who's operated on a patient with the disease: omental caking. Most textbooks will describe the phenomena as a principle and often-seen characteristic of the disease at presentation.4 It is also frequently cited as the source for ascites and a rationale for cytoreduction, because the largest extra-ovarian tumor collection is usually housed there.5-7 I recall frequently explaining to the patient, trainees, and colleagues that the propensity of implantation in the omentum is due to its large surface area, its rich blood supply, and its function in peritoneal fluid dynamics. However, the relative lack of implants on a similarly large surface area, the intestinal mesentery, suggests my explanation is incomplete. The paper by Nieman and colleagues clearly demonstrates that omental fat cells are unique and instrumental in driving the tropism of ovarian cancer cells to the organ. Not only do the omental fat cells draw ovarian cancer cells to them by secreting an important cytokine (IL-8), they also provide nutrition (lipids) and support for the mass to grow and spread. A critical feature in this process is expression of the FABP4 gene, which goes into "overdrive" when the two cell types meet up. When omental adipocytes are modified to not express FABP4, tumor growth and metastasis is nearly completely prevented, suggesting the gene is a very important element of ovarian cancer biology. It also provides support for omental resection in cases where disease appears limited. While this is routinely performed as a matter of staging (occult disease), the functional implication is that retention could provide support for subsequent tumor growth. Indeed, unstaged patients with clinically stage I disease (disease limited to the ovaries) who are not treated with adjuvant chemotherapy have a clinical course not dissimilar to advanced stage disease patients when they recur. This has prompted prophylactic adjuvant therapy in such cases.8 In contrast, fully staged patients with stage I disease may not benefit from adjuvant therapy and may be cured with surgery alone.9
As enticing as the data are in this report and the degree to which the new explanation goes to describing an event we see every day with the disease, it has to be tempered by the plethora of similarly claimed new "regulators of tumor biology" being increasingly described. As a matter of practicality, we as clinicians and investigators need to understand how to leverage the emerging data set into everyday treatment approaches for our patients. However, the mining of data from the TCGA project and incorporation of the resultant hypotheses into meaningful preclinical investigation will be the genesis of tomorrow's treatment.
References
- Hennessy BT, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 2010;28:3570-3576.
- Fong PC, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-134.
- Audeh MW, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009; 27:15s (suppl; abstr 5500).
- Gerber SA, et al. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol2006;169:1739-1752.
- Zivanovic O, et al. The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC ovarian cancer stratified by the initial tumor burden in the upper abdomen cephalad to the greater omentum. Gynecol Oncol 2010;116:351-357.
- Naik R, et al. Complete cytoreduction: Is epithelial ovarian cancer confined to the pelvis biologically different from bulky abdominal disease? Gynecol Oncol 2000;78:176-180.
- Eisenkop SM, et al. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: Impact on survival. Gynecol Oncol 1993;51:224-229.
- Le T, et al. The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma. Gynecol Oncol 2002;85:351-355.
- Kolomainen DF, et al. Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 2003;21:3113-3118.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content