Systemic Cancer Progression and Tumor Dormancy: Mathematical Models Meet Single Cell Genomics

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1 Cell Cycle ISSN: (Print) (Online) Journal homepage: Systemic Cancer Progression and Tumor Dormancy: Mathematical Models Meet Single Cell Genomics Christoph A. Klein & Dieter Hölzel To cite this article: Christoph A. Klein & Dieter Hölzel (2006) Systemic Cancer Progression and Tumor Dormancy: Mathematical Models Meet Single Cell Genomics, Cell Cycle, 5:16, , DOI: /cc To link to this article: Copyright 2006 Landes Bioscience Published online: 02 Aug Submit your article to this journal Article views: 363 View related articles Citing articles: 45 View citing articles Full Terms & Conditions of access and use can be found at

2 [Cell Cycle 5:16, , 15 August 2006]; 2006 Landes Bioscience Spotlight on Cancer Cell Dormancy Systemic Cancer Progression and Tumor Dormancy Mathematical Models Meet Single Cell Genomics Christoph A. Klein 1, * Dieter Hölzel 2 1 Institut für Immunologie; Ludwig-Maximilians-Universität; München, Germany 2 Munich Cancer Registry; Institut für Medizinische Informationsverarbeitung; Biometrie und Epidemiologie (IBE); Klinikum der Ludwig-Maximilians-Universität; Großhadern, München, Germany *Correspondence to: Christoph A. Klein; Institut für immunologie; Ludwig- Maximilians-Universität; München, Goethestr. 31; München, Germany; Tel.: ; Fax: ; christoph.klein@ med.uni-muenchen.de Previously published online as a Cell Cycle E-publication: KEY WORDS breast cancer, metastasis, tumor dormancy, minimal residual disease, micrometastasis, clinical progression ABSTRACT Metastatic progression is thought to result from genetically advanced fully-malignant tumor cells. Within the concept the prevailing view holds that such cells disseminate mostly from large tumors and are capable of growing into metastases once they arrive at a distant site. Support for this scenario comes from numerous mouse models in which transplanted tumor cells grow into metastases within days or weeks. However, the assumption of such fully-malignant disseminating cells in human cancer is misleading and is neither supported by mathematical modeling of survival data from cancer patients nor by ex-vivo genomic data from disseminated cancer cells. For example, in breast cancer the growth of metastases is highly homogeneous and takes on average six years, the number of disseminated tumor cells before diagnosis of metastasis is similar for different tumor stages, and the genomic aberrations of disseminated cancer cells do rarely correspond to those in the primary tumor. Since these facts question conventional concepts of metastatic progression we provide a model of cancer progression in which time considerations and direct ex-vivo data form a starting point. In the proposed model tumor dormancy is a characteristic of almost all migrated tumor cells and metastatic growth is a rare, stochastic, evolutionary process of selection and mutation of cells that often disseminate shortly after transformation at the primary site. INTRODUCTION Tumor dormancy is a well-known clinical phenomenon of which the underlying mechanisms are poorly understood. It commonly designates latency periods of cancer growth lasting from the surgical resection of the primary cancer until the clinical appearance of local or distant recurrences. The term dormant cancer cell dates back to the first half of the 20 th century and may have been coined by the Australian pathologist Rupert A. Willis. 1 Although there is no precise definition, cancers were called dormant if the latency period exceeded 5-6 years, because it was difficult to believe that cellular proliferation of residual tumor cells had been continuous and uninhibited for such long periods. 2 During the following 50 years several hypotheses on possible causes for the growth arrest have been proposed, including unfavorable growth conditions imposed by the ectopic microenvironment, some sort of cancer immunity, or the inability of the disseminated cancer cells to induce angiogenesis. The topic of this review is to gather the available evidence that the mechanisms of tumor dormancy, and thus the term itself, do not only apply to the interval from surgery of the primary tumor until the resurgent growth of the cancer cells, but are active from the very beginnings of the disease itself. Thereby, we present a general model of systemic cancer progression with fundamental implications for clinical and experimental cancer research. EPIDEMIOLOGY OF BREAST CANCER PROGRESSION 2006 LANDES BIOSCIENCE. DO NOT DISTRIBUTE. Clinical databases. Since tumor dormancy is defined by the duration of silent periods of tumor growth (> 5 yrs.), experimental models will inevitably fall short in their capability to analyze and explain the phenomenon. Clinical data following the fate of cancer patients therefore provide the theoretical background of all attempts to understand the potential mechanisms. The Munich Cancer Registry (MCR) collected follow-up data of more than 320,000 cancer patients and includes more than 20,000 newly diagnosed patients every year. Since long latency periods are not uncommon in breast cancer most of the clinical findings discussed below are based on the analysis of breast cancer patients, for which survival data of 25,588 patients were available (Fig. 1A) Cell Cycle 2006; Vol. 5 Issue 16

3 Figure 1. Clinical course of breast cancer. (A) Relative survival of breast cancer patients for the different tumor stages. After 20 years, 20% of pt1, 50% of pt2, and 80% of pt3/4 patients will have died. (B) Calculation of the duration of metastatic growth. Regardless of tumor stage and time point of diagnosis the time interval between diagnosis of metastasis (rectangles) and death (circles) is homogeneous. With assumption of a symmetrical time distribution and with the median time to metastasis, one can estimate the growth time of a metastasis to approximately six years. Thus the curve is shifted to the left to indicate the average time of initiation (triangles). Examples of three patients are fitted into the diagram, with patient A diagnosed as M1 at primary diagnosis, patient B with a two-year metastasis-free interval, and patient C with a six-year metastasis-free interval. In patient A the metastasis was initiated six years, in patient B four years before diagnosis of the primary tumor. In patient C metastatic growth was initiated just before removal of the primary tumor (M, diagnosis of metastasis; D, death of patient; dashed vertical line, diagnosis of primary tumor). (C) Cumulative time distribution until diagnosis of metastasis for pt1, pt2, and pt3/4 tumors. Note that 50% of patients with pt3/4 tumors already present with metastatic disease. (D) The survival of breast cancer patients without a local relapse can be described by exponential functions (red lines). Note that there is no flattening of curves of pt1 or pt2 at five or six years which would indicate a changed hazard ratio for clinical dormancy. Thus, the death rate from breast cancer represents a homogeneous process. The time course of metastatic growth. If dorm-ancy is an unusually long latency period until secondary tumor growth, it should be contrasted with the normal time interval between tumor excision and secondary tumor growth. Secondary tumors can either arise as distant metastasis or within the proximity of the primary growth (local or regional metastasis). In general, three types of regional and distant progression are observed. Metastasis may be detected after primary therapy (metachronous metastasis), or may already be present at diagnosis of the primary tumor (including lymph node positive (N+) or distant metastasis (M1) patients), or, last but not least, may be diagnosed in absence of a primary tumor (so-called cancer of unknown primary, 3 CUP, with or without later identification of the primary tumor). Interestingly, there are no remarkable differences in survival between CUP from mammary cells, breast cancer patients with distant metastasis at diagnosis of the primary tumor, or with metachronous distant metastasis, suggesting that disease progression after detection of metastases is rather homogeneous. This observation provides a first way to calculate the time required for metastatic growth. 4 After diagnosis of metastasis the median survival of breast cancer patients is remarkably stable lasting about 24 months (Fig. 1B). Only a two-fold variation is found indicating that after initiation of a metastasis the process is largely autonomous. Apparently at this stage biological differences between individual breast cancers are rather small and the growth rate is independent from tumor size at diagnosis, histo-logical grade, or hormone receptor status. Moreover, metastatic progression after diagnosis of a metastasis does not depend on whether or not the patient presented with metastasis at primary diagnosis neither on the duration of the metastasis-free survival or any other prognostic factors. 4 Since all these factors vary ten- to twenty-fold in their ability to predict risk for death from cancer, the duration of metastatic growth is best estimated by using the time from diagnosis of metastasis to death. It is also reasonable to assume that the process of metastatic growth is as homogeneous before diagnosis of metastasis Cell Cycle 1789

4 as it is afterwards. Thereby we get a rough approximation on how long migrated tumor cells grow to a detectable metastasis. For example, median distant disease-free survival time for pt1-patients (pt1 is a tumor of less than 2 cm diameter) is about three years (Fig. 1C). Compared with metastases that are already present at diagnosis of a pt1 tumor (i.e., a patient staged as pt1 M1) these metastases apparently were initiated three years later. Under assumption of a symmetrical time distribution, initiation of the metastasis must have taken place at minimum six years ago. Therefore, by simply shifting the curves for metastasis on the time axis (Fig. 1B), it becomes evident that the longer metastasis- free survival time for pt1 tumors in comparison with pt2 and pt3 tumors represents a lead-time effect. The larger tumors are simply growing for longer time and the lead-time represents the time that is needed for the pt1 tumor to become as large as pt2 or pt3 tumors (see also Fig. 2A). Support for the assumption of a rather homogeneous growth pattern of metastatic colonies is provided by the analysis of time to metastasis after diagnosis of the primary tumor (Fig. 1C). For clinically detectable tumors the duration of metastatic growth until detection of a metastasis is independent from tumor size and a comparable risk for metastasis is observed without discontinuity until 5 6 years after diagnosis of the primary tumor (Fig. 1C). This also indicates that once metastases have started to grow, further development is homogeneous before and after diagnosis of metastases. From the follow-up data of the patients there is also no evidence for an increase in the hazard rate at five or six years, which had been taken as evidence for tumor dormancy before. 5,6 If only patients with a single breast cancer are included into analysis, the survival can be described by an exponential function quite accurately for pt1 and pt2 tumors, indicating a homogeneous natural process (Fig. 1D). The assumption of a homogeneous progression (in the statistical mean) does not imply a homogeneous and continuous development of metastasis. Metastasis is a complex process and tumor cells have to take several hurdles, such as homing to an organ, resistance to anoikis (i.e., apoptosis induced by the environment) at the ectopic site, first colonization, and establishment of blood supply, until metastases are diagnosed. 7 In contrast, the estimated time for the duration of metastatic growth (i.e., six years) is calculated from successful initiation and thus necessarily provides the shortest possible time estimate for metastases to grow. We will see below that initiation of metastatic growth is not equivalent to dissemination of tumor cells. Primary tumor size and metastasis. For most cancer types metastasis and prognosis are directly associated with tumor size, i.e., the larger the tumor the higher the risk to develop and die from metastases (Fig. 1A). Above we compared small and large tumors with metastases and observed first, no difference for the time to death and second that the earlier emergence of a metastasis in the clinical course simply reflects the fact that a large tumor has grown longer before detection than a small tumor (Figs. 1B and 2A). This justified setting the metastatic growth until diagnosis of any breast cancer metastasis to approximately six years. What is then the nature of the relation of tumor size and metastasis? Most often the association of tumor size and metastasis is taken as evidence for the higher rate of dissemination of metastatic cells at later tumor stages. This assumption is certainly not convincing for patients that present with metastasis at diagnosis. For a pt1/ M1 tumor of 1.5 cm diameter, having an approximate volume of 1.8 cm 3, one can calculate the number of cells at which the metastasis-initiating tumor cells disseminate. Since 1 cm 3 is equivalent to about 10 9 cells, a pt1 tumor comprises cells. If we assume 12 cell doublings in six years, the population was about Figure 2. Tumor size, initiation of metastasis, and tumor cell dissemination. (A) Cell numbers in primary tumor and initiation of metastasis. The lead-time of a pt3 tumor to a pt1 tumor is the time that is needed to grow to the larger size. Since, in the example, metastases were initiated at the same tumor size (arrow), the metastasis-free interval of the pt3 patient is reduced by the lead-time. The width of the cone indicates the increased risk for the patient with the pt3 tumor to develop metastasis. The lower panel depicts three individual patients. In patient A metastasis was initiated at a small tumor size and was diagnosed together with the primary tumor, while patient C had a detectable tumor when the metastatic growth was initiated (>10 9 cells) and had a long metastasis-free interval. (B) The number of disseminated cells does not significantly increase with growing tumors. Detection rates of cytokeratin-positive cells per 10 6 bone marrow cells for pt1, pt2, and pt3/4 tumors. In this group of patients (n=299; pt1, 45%; pt2, 35%; pt3/4, 11%) detection rates were 24%, 27%, 29%, respectively, and the number of patients with more than 2 cells per 10 6 bone marrow cells was 8%, 6%, and 10% for pt1, pt2, and PT3/4, respectively. cells, when the metastatic precursor cell left the primary site, equivalent to a lesion of 1 mm diameter. If we do the same calculation for larger tumors, e.g., pt2/m1 (3 cm) and pt3/m1 (5.5 cm), the metastastic precursor cells would have left the primary tumors when they comprised and , respectively. The simple calculations already reveal a very puzzling fact: Since about 50% of patients with pt3/4 tumors present with manifest metastasis at diagnosis of the disease (Fig. 1C), these metastases were derived from lesions that were maximally 3 mm in diameter ( cells) and thus undetectable by standard clinical imaging. Only for the remaining 50% we may speculate that the metastatic cells disseminated when the tumor had a detectable size (Fig. 2A) Cell Cycle 2006; Vol. 5 Issue 16

5 For patients with metachronous metastases things seem to be more complicated. First, we have to note that the association of tumor size and metastasis is strictly linear within normal ranges and increases with the diameter of the tumor and not with its surface or its volume, for which it should be quadratic or cubic, respectively. After surgery patients with pt1 tumors will develop metastases in 20%, with pt2 tumors in 50% and with pt3/4 tumors in 80% of cases after 20 years (Fig. 1A). Therefore, while we hardly detect any biological differences in growth behavior once metastases are established, the discrepancy that large tumors need longer to generate a cell capable to metastasize than small tumors (a pt3 tumor comprises about 50 times more cells than a pt1 tumor) but kill more frequently (but only 4 times more frequently), needs to be resolved. Apparently, the search for the biological differences between tumors should concentrate on the period of seed and first colonization. Tumor dormancy as the absence of growth may then explain the differences between tumors. THE PREVAILING VIEWS ON PROGRESSION AND TUMOR DORMANCY More cells more risk: the stochastic model. This view holds that the larger the tumor the more tumor cells disseminate and therefore the chances should be higher that one of these cells eventually grows into a metastasis. However, the linear association of tumor size and metastasis already indicates that metastasis is a very rare event and that almost all tumor cells are unable to metastasize, 8 because tumor volume gives the most accurate estimate for the total number of cells in a tumor. In this concept, those 20% of patients with small tumors (pt1) that died from metastasis just had bad luck with the very unlikely event that a tumor cell disseminated. At a larger size (pt3), disseminating cancer cells are thought to be produced with higher frequency and therefore the chances that one of them will grow into metastasis is higher. It will be shown below that the basic assumption for this concept, i.e., higher number of tumor cells disseminating from large tumors, cannot be verified for human breast cancer. Late metastasis of fully malignant cells: the linear progression model. Since the lack of a cubic association of tumor size and metastasis indicates that not all tumor cells are alike, grades of malignancy were introduced. Cancer metastasis is often seen as the final step of the local transformation process of tumor cells from bad to worse, with a metastasizing cell as being fully malignant. Genetic data, as depicted in the famous Vogelgram, seem to fit nicely into that concept. 9 Originally deduced from the genetic analysis of the different morphological stages of colorectal cancer development, the step-wise accumulation of genetic changes in local cancers was also extrapolated to systemic spread. Starting from normal, loss of the adenomatosis polyposis gene (APC) located on chromosome 5q seemed to precede mutations in the KRAS oncogene and the TP53 tumor suppressor gene. After these and other events had taken place, cancer cells were thought to disseminate and form distant metastases. Bert Vogelstein and colleagues suggested upregulation of the phosphatase PRL-3 to initiate the metastastic spread. 10 During the last decades, disciples adopted the model for all major types of solid cancers and several metastogenes have been proposed. The genetic data were compatible with older studies on the metastatic progression. By transplantation studies of mouse tumors I. Fidler had previously identified the metastastic insufficiency of most cancer cells and suggested that few variant cells within the primary tumors are capable to metastasize. 11 Variant cells would then represent those cells that had acquired the genetic changes enabling dissemination and metastatic outgrowth. In a combination with the stochastic model, this concept suggests that the likelihood of a fully-malignant cell to develop is higher in a large tumor. For tumors of or tumor cells (the 1 mm or 3 mm lesions, respectively, that are seeding tumor cells and are diagnosed as pt1 M1 or pt3/4 M1 cancer six years later) the chances that a fully-malignant cell develops and disseminates appears to be higher for the larger population. While possibly acceptable for the difference of 1 mm and 3 mm lesions, it becomes somehow miraculous that a patient that is operated for a pt2 tumor (3 cm) and is diagnosed with metastasis six years after surgery had to build a population size of cells before a cell capable of metastatic dissemination was generated (Fig. 2A). Therefore, in the fully-malignant-cell concept, the biological differences between tumors seem to be reflected by the number of cells that need to be produced until a fully-malignant cell has accumulated critical genetic changes. However, to date no genetic or epigenetic change has been identified which could account for these enormous differences (a factor of 35,000 (1.4 X divided by 0.4 X 10 6 ) for pt1/m1 vs. pt2/m0 tumors) in seeding efficiency, although a molecular comparison of pt2 tumors without metastasis for the next six years after surgery to a pt1 M1 tumor should uncover remarkable differences. Surprisingly little attention has been paid to considerations about time and population size in the discussed concepts. Another difficulty in the fully-malignant-cell concept is that tumor cells isolated from patients are rarely fully malignant. While in mice tumors from cell lines grow within weeks they apparently did not so for many years in their favorite environment, i.e., the patients they were isolated from. While evidence for immunosurveillance mechanisms in cancer is scarce, 12 a seemingly plausible answer to this paradox was provided by the concept of the angiogenic switch. 13 It had been observed that the induction of an adequate blood supply is necessary for growing tumor cells, which become apoptotic if located more than 100 µm from a supplying vessel. 14 It was assumed and subsequently shown in transplantation experiments 15 that inoculated cancer cells are at least initially incapable of inducing angiogenesis, but constantly proliferating and forming colonies up to a critical size and then become apoptotic. 16 In theory, this process could take many years until the cells acquire an angiogenetic phenotype and induce new blood vessels. While being intuitively acceptable at first sight, this explanation implicates that in human disease mostly those cancer cells disseminate that are poor inducers of angiogenesis although they are thought to stem from large, highly vascularized primary tumors, composed of tumor cells that display a rather advanced genotype and phenotype. Metastasis from metastasis? The skepticism about a model in which increasingly malignant cancer cells disseminate at late tumor stages is fueled by the lack of evidence for metastasis from metastases 17 because -according to the model- tumor cells from metastases should grow significantly more easily, i.e., faster, to manifest metastases. The clinical data do not support the opinion that metastasis from metastasis takes place in patients and is relevant for disease outcome. Multiple, synchronous or metachronous organ metastases do not follow a structured course of events. Moreover, the intervals between the detection of two different sites of metastatic manifestation are far too short when compared to the calculated time from initiation to manifestation. For example, 50% and 90% of primary bone metastases are estimated to have grown within 36 and 104 months, respectively, until detection. The comparable data for lung Cell Cycle 1791

6 Table 1 Time to metastasis for breast cancer patients (stage M0) when first metastasis is restricted to only one organ or diagnosed as multiple metastases. (Median and time until 90% of patients have developed metastases). Metastasis in Only One Organ Metastases in Multiple Organs Localization n Median in 90% Percentile n Median in 90% Percentile of Metastasis Months in Months Months in Months liver ,9 84, ,0 82,8 lung/pleura/trachea ,1 97, ,8 111 distant lymph nodes , ,6 93,9 skeleton/bone , ,5 96,7 central nervous system , ,9 81 skin , ,2 86 other , ,7 133 metastasis and metastases to the central nervous system are 32/97 months and 32/105 months (Table 1), respectively. In a cascade model, in which the first metastasis seeds the second and so on, the time distribution for the second metastasis would have needed a time translation, or a much higher growth rate would be necessary for the second and third generation metastases. Since this is highly unrealistic (because as stated before growth of metastases is very homogeneous) and is, to our knowledge, not supported by any histopathological data (such as increased numbers of mitotic figures or higher labeling indexes for KI67 in the second metastasis than in the first metastasis), it seems more plausible that different metastases including local and regional metastases are derived from independent cancer cells that disseminated from the primary lesion. Indirect support for this view comes from follow-up data: diagnosis of synchronous metastases in multiple organs is not a sign for more aggressive growth than is diagnosis of a single metastasis, because the time to diagnosis of metastases after surgery is similar for the two groups of patients (Table 1). Finally, recent data from therapeutic trials also do not support the metastastic cascade model. While anti- HER2 directed therapy using the antibody trastuzumab seems to efficiently delay peripheral metastases, a higher risk for metastases in the central nervous system is observed. 18,19 If the brain metastasis would be derived from peripheral metastases, one should also observe a decrease in brain metastases. CHALLENGING THE TRADITIONAL VIEWS ON METASTATIC PROGRESSION: DIRECT ANALYSIS OF DISSEMINATED CANCER CELLS The two traditional models comprise two testable hypotheses. The first model (i.e., that more tumor cells disseminate from larger tumors) may be tested by counting disseminated tumor cells. The second model, the concept of disseminating fully-malignant tumor cells postulates that the disseminated cancer cells are in a further progressed genetic stage than the primary tumor, because accumulation of genetic changes is thought to underlie progression. The combination of both models eventually predicts that at the time of surgery of the primary tumor, the majority of disseminated cancer cells are genomically further progressed than the predominant population of the primary tumor and that in patients with larger tumors more tumor cells and more advanced tumor cells will be detected. The extent of dissemination. In breast cancer and other types of carcinomas, disseminated cancer can be detected long before manifest metastasis in bone marrow or lymph nodes at the time of primary surgery. These tumor cells may comprise the metastatic precursor cells since their detection confers a high risk for metastatic relapse. 20 As carcinomas are derived from epithelia and epithelial cells are absent from mesenchymal organs like bone marrow, lymph nodes, and blood, histogenetic markers, such as cytokeratins, can be used to specifically stain disseminated carcinoma cells in these organs. Several assays for the detection of disseminated cancer cells have been developed and have been reviewed before. 21,22 Usually, 1 2 cytokeratin-positive cells are detected per 10 6 bone marrow cells in every third patient that is clinically free of metastasis at surgery. During progression a statistically significant association is seen between positive bone marrow samples screened for single disseminated cancer cells and tumor stage, increasing from 25% of patients with tumors of 1.5 cm (pt1) in diameter to about 38% in nonmetastatic patients with tumors larger than 5 cm in diameter (pt3). 20 However compared with total numbers of cells in the primary tumors, which rise more than 37-fold, this seems to be a rather small increase. Moreover, an increase of disseminated tumor cells per million bone marrow cells with increasing tumor size in positive patients is not observed (Fig. 2B). This finding has several implications. First, the rate of dissemination is very weakly linked to the number of cells in the primary tumor if at all. We previously noted that tumor size and metastasis are associated only in a linear mode and now it appears that dissemination and tumor size is associated less than linear (in linear association the detection rate should be about 75% instead of 38% for pt3 tumors). Second, we can calculate the number of disseminated cancer cells in bone marrow. In adults the volume of bone marrow is about 1.5 L. Using Ficoll for density gradient centrifugation on average cells/ml are isolated. Ficoll is known to deplete 70 90% of bone marrow cells, mostly granulocytes. Therefore, 1 ml bone marrow may contain cells. On average, in breast cancer patients with a positive assay 2.2 cytokeratin-positive cells are found in 10 6 bone marrow cells. If we assume that all these cells are tumor cells and that the recovery rate for tumor cells is 50%, 1 ml bone marrow would contain 4 18 tumor cells before centrifugation on Ficoll. Thus, total bone marrow could contain between 6,000 and 27,000 tumor cells from which one or few bone metastases would grow during the lifetime of a patient. If the sensitivity of the 1792 Cell Cycle 2006; Vol. 5 Issue 16

7 detection assay is about 10,000 disseminated cancer cells per patient, additional 13% of patients take this threshold during the progression from stage pt1 to pt3. Third, with this threshold the number of migratory cells is 1 per tumor cells for pt3 tumors and 1 per 1.7 x10 5 for pt1 tumors. Thus, the discrepancy between the total numbers of tumor cells on one hand and evidence of dissemination suggests that the cells capable to successfully disseminate or grow into metastases decrease 38-fold as the cancer grows. Taken together, the hypothesis of higher numbers of disseminating cancer cells as cause for the association of tumor size and metastasis is not supported by clinical nor ex-vivo immunocytochemical data. Genomic analysis of disseminated cancer cells. With these data, not only the stochastic model of progression but also the full-malignant cell hypothesis is weakened. If migratory behavior is included into the definition of a fully-malignant cell, we find that the larger the tumor the lower the relative number of migratory tumor cells although huge numbers of tumor cells generated at the primary site presumably contain more genetic aberrations. This unexpected result calls for a direct genetic analysis of disseminated cancer cells. Before we discuss the genetic data, we should consider the following. If a breast cancer metastasis needs on average six years to grow, then a metastasis is derived from a tumor cell population that existed at least six years before. In theory, this could be the tumor cell population in the paraffin-block if the metastasis emerges six years after surgery. However, we can safely state that the genetic changes of lesions that seeded the metastatic cells of patients with pt1 M1 of pt3/4 M1 at primary diagnosis are not known at all. Lesions of 1 mm or 3 mm diameter (the approximate size of these tumors at seeding), respectively, cannot be diagnosed with current imaging techniques and therefore we simply do not know their cellular composition. Since many cell divisions have taken place and genetic instability might have changed completely the cellular composition of the original lesion, the detected primary tumor is likely to be genetically very different. At least there is no data showing that the tumor cell population forming the primary tumor (or the metastasis) at diagnosis is still similar to the one that existed six years before. When we started to analyze the genomes of disseminated cancer cells, we found in breast cancer, but also in other cancer types studied so far (unpublished data), remarkable differences for chromosomal abnormalities 23 between primary tumors and the tumor cells that were isolated from bone marrow of patients without manifest metastasis. Indeed, the tumor cells taken from bone marrow harbored significantly less genomic aberrations than the primary tumors. We had developed a protocol that enables the application of comparative genomic hybridization (CGH) to single cells and to microdissected material from paraffin-embedded primary tumors. 24,25 For example, only in 14% of M0-stage breast cancer patients with single chromosomally abnormal disseminated cancer cells in bone marrow we could detect shared aberration between primary tumors and the analyzed cytokeratin-positive cells. 23 However this number is calculated using only those cases where we could detect cytokeratin-positive cells that displayed chromosomal abnormalities. In more than 50% of cytokeratin-positive cells isolated from bone marrow of breast cancer patients without manifest metastasis, no such CGH abnormality was found, while the matched primary tumors regularly harbored them. 23,26 When we analyzed these normal appearing cells at higher resolution for small DNA deletions or amplifications (CGH detects only losses of 10 Mb, while microsatellite PCR or SNP analysis detects changes of about 1 kb) we observed that most of these normal appearing cells are indeed Figure 3. Genomic comparison of a primary tumor (pt2) and a cytokeratin-positive cell isolated from the bone marrow of the same patient. (A) Chromosomal abnormalities in the primary tumor. Gains are indicated for each chromosome by green bars on the right side, losses by a red bar on the left side of the ideogram. The gray shaded areas are excluded from evaluation. (B) A normal CGH profile was found for the cytokeratin-positive cell in bone marrow. (C) The cell shown in B displays several allelic losses detected at higher resolution. In addition, this tumor cell harbored a HER2-amplification on chromosome 17q12-21, as detected by qpcr. 26 Note the deleted region on chromosome 16 between the SNP marker rs14212 and the microsatellite marker D16S3066 (red, allelic loss; green, no loss; gray, marker not informative). Cell Cycle 1793

8 tumor cells derived from breast cancers 26 (Figs. 3A C) Therefore, in at least 95% of cases no similarity for chromosomal aberrations could be established between the primary tumors and cytokeratin-positive tumor cells in bone marrow of breast cancer patients. Interestingly, chromosomal abnormalities (i.e., those that are detected by CGH) are thought to occur at the transition of ductal hyperplasia to in-situ carcinomas, i.e., at a stage when the tumors are histologically not yet invasive. 27 The finding of tumor cells without CGH aberrations in bone marrow suggests either that mostly cells without such changes disseminate from an invasive primary tumor (where they certainly represent a minority of the cell population) or that dissemination starts before pathologists observe invasiveness. The latter would certainly question the dogma that a microscopically intact basement membrane prevents dissemination of breast cancer cells. In summary, the model of linear progression is challenged by the following facts: First, since CGH detects genetic changes that are present in at least 60% of primary tumor cells, this predominant cell population disseminates only exceptionally. Although the percentage of tumor cells without CGH abnormalities in a primary tumor is unknown, it is reasonable to assume that such cells if existing are very rare. Second, since disseminated cancer cells display lower numbers of genetic changes per cell than the primary tumor cells, this likely reflects that they are not derived from the primary tumor as it is found at diagnosis. Rather, they may originate from earlier stages of the cancerous lesion. Third, both the reduced relative number of migrating cancer cells in large tumors and the absence of typical genetic changes in the disseminated cancer cell population suggest, that the cells in the primary tumor are highly selected for stationary growth and mostly unable to disseminate. Thus, there is no evidence of genetically more advanced, fully-malignant cells giving rise to human breast cancer metastasis. Progression of Systemic Disease. At the time of surgery of a primary tumor, more than 95% of disseminated breast cancer cells in bone marrow display either none or compared with the matched primary tumors fewer or different chromosomal abnormalities. For all patients several years will pass until they develop metastatic disease. The findings from disseminated tumor cells suggest the possibility that the long time interval is needed to accumulate those genetic changes required to grow into metastasis. Most likely, early-disseminated cancer cells have to progress through the Vogelgram at the distant site as they do at the primary site. Since most cancer types from different patients concur on a restricted cast of chromosomal abnormalities 28 one would expect at least some of later emerging metastases to converge on similar chromosomal aberrations as the primary tumors. This is indeed the case for about 50% of breast cancers. 23,29 When we could detect and analyze more than a single disseminated tumor cell, the cytokeratin-positive cells isolated from patients without manifest metastases displayed very different chromosomal changes as long as the patients remained in the stage of minimal residual disease. However, in more than 95% of patients who presented with manifest metastases the individually isolated and analyzed cytokeratin-positive cells from bone marrow were highly similar. 30 This suggests that early-disseminated tumor cells being genetically unstable, diverge considerably until one clone acquires genetic abnormalities enabling colonization and growth at a distant site. Since the detection of clonal expansion was in our study associated with the detection of clinically manifest metastases, the last step might indeed evolve quite rapidly. For a definite answer whether linear (such as step-wise accumulation of genetic changes) or nonlinear processes (for example sudden events like acquisition of a critical mutation, cell fusion 31 or other) drive the generation of clonally expanding cells, one should longitudinally study disseminated tumor cells from bone marrow of cancer patients. ATTEMPTING A SYNTHESIS: CLINICAL DATA AND SINGLE CELL BIOLOGY Large epidemiological data sets and the direct analysis of metastatic precursor cells apparently are consistent and coherent in many aspects (for a comparison of the discussed models, please see Table 2). First, a rational model of breast cancer progression includes that the first metastases are initiated years before diagnosis of the primary tumor when the tumor is rather small. The direct analysis of disseminated cancer cells supports this by the detection of disseminated tumor cells in bone marrow that are genomically far less progressed than the cells from the primary tumor at diagnosis. Obviously, these cells were slowed down in their progression as compared with the cells in the primary tumor. Second, calculated growth kinetics do not support the hypothesis that further progressed and rapidly dividing cancer cells disseminate from large tumors and grow out to metastases (neither for the first metastases nor for following metastases) nor are tumor cells detected at peripheral sites that are genetically equally or even further progressed than the primary tumor in sufficient numbers of patients. Third, the duration of growth of a metastasis (about 6 years) is shorter than the total time of systemic disease. The event that a disseminating cell immediately grows at the distant site obviously is quite rare and therefore initiation of metastatic growth is not equivalent to dissemination. More often early-disseminated tumor cells get arrested after homing to a distant site and this state could be designated as cellular dormancy. To date there is no information about the nature of this cellular dormancy in human cancer, whether the cells are arrested in the cell cycle or whether some cell turnover facilitates the accumulation of additional hits. If the accumulation of genetic changes for successful colonization and metastatic outgrowth is an intrinsic stochastic process, large variation of time courses is to be expected. Clinical dormancy would then represent patients with disseminated cells that start to grow very late and those patients appear as the outliers of the normal progression, constituting the long right-hand tail of the time distribution. Reconsideration of the fully-malignant cell-concept. The concept of a fully malignant cell seems to be adequate only in those cases where metastastic growth is initiated very rapidly after dissemination. This may apply to the rare cases of pt1 M1 or patients with CUP. For other patients, the hypothesis of a genetically advanced fully- malignant cell from a large tumor that alone is capable to disseminate and grow into metastasis may only be saved by postulating that cytokeratin antibodies regularly fail to identify the relevant (i.e., metastatogenic) tumor cells or by stating that they hide in organs different from bone marrow. Downregulation of cytokeratin has been observed in primary breast cancers 32 and may be associated with the process of epithelial-mesenchymal transition. 32,33 If cytokeratins are downregulated in disseminated cancer cells we might underestimate the number of disseminated cancer cells. However, in clinical stage M1 numerous cytokeratin-positive cells with chromosomal aberrations (> 90% of these cells display CGH abnormalities) are regularly observed in bone marrow of breast cancer patients. Therefore, it is unlikely that the antibody selectively stains tumor cells without chromosomal abnormalities specifically in clinical stage M0. In addition, while absolute numbers in our calculations may differ, the ratios between disseminating and stationary tumor cells 1794 Cell Cycle 2006; Vol. 5 Issue 16

9 Table 2 Models of cancer progression and tumor dormancy Model Supporting Data/ Conflicting Data/ Tumor Dormancy Advantages of Model Difficulties of the Model Stochastic model Prognosis is associated with Tumor size, N- or M stage, or survival are Dormancy is the likely tumor size associated only linearly. No association to outcome in the rare event of tumor volume (i.e., cell number) is observed. dissemination. Probability to Def.: Larger tumors Simple model overcome dormancy seed more cells which Does not account for homogeneous 6-year depends on numbers of results in higher risk growth period of metastases. disseminating tumor cells. for metastases. Number of disseminated cancer cells in BM is Implications: not associated with tumor cell numbers. Number or rate of disseminating cells Percentage of migrating tumor cells from increases with large tumors is smaller than in small tumors. tumor size. Disseminated cancer cells in bone marrow display different aberrations than predominant cell population at primary site. CUP syndrome comprising 5 10% of diagnosed patients cannot be explained. Linear progression model Prognosis is associated with Duration of growth of metastasis is Dormancy is the (unlikely?) tumor size independent from primary tumor size. event that a fully-malignant cell is not fully malignant and Def.: Tumor cells Evidence that genetic changes Does not account for homogeneous stops growing at the ectopic accumulate somatic accumulate at primary site 6-year growth period of metastases site. mutations at the (e.g., adenoma-carcinoma primary site and sequence). Metastasis-free interval is explained by disseminate from large lead-time effect not by higher aggressiveness established tumors. May explain the lack of cubic Dissemination of association of metastasis with No evidence for higher numbers of fully-metastatic cells. primary tumor size: invasive genomically advanced tumor cells at properties are acquired late ectopic sites. Implication: Late and at random and part of disseminating tumor cells fully-malignant cell. Comparison with primary tumor reveals are more aggressive, have less and different genetic changes of more genetic changes, disseminated cancer cells. and disseminate more frequently from larger Large (genetically advanced) tumors produce fewer disseminating cancer cells. Cannot explain lack of clinical evidence for metastasis from metastasis. CUP syndrome comprising 5 10% of diagnosed patients cannot be explained for the different tumor stages would still remain similar. The hypothesis of a specific metastatic niche outside the bone marrow from where a sudden colonization of bone takes place that regularly escapes detection during clinical stage M0, is not very convincing. Skeleton is the most frequent metastatic site in breast cancer (Table 1) and bone marrow has been shown to attract mammary tumor cells by specific mechanisms. 34 The concept of the fully-malignant metastatic cell considers cancer progression as a cell-autonomous process. However, cancers progress in an organism and as such are subject to complex cellular interactions. These interactions are - as is the cellular development of the cancer cell itself - dependent on the genetic background of the patient and on environmental influences. Dissemination obviously occurs with high frequency early in the transformation process and the disseminated cancer cells have to overcome the cellular control mechanisms similar to the tumor cells growing at the primary site. We therefore suggest that almost all disseminated tumor cells will be arrested in dormancy after homing at the distant site. Cellular dormancy has to be overcome for the tumor cells to accumulate additional aberrations and the release from dormancy is somehow associated with the size of the primary tumor (see below). Disease progression, disseminated cancer cells and metastatic stem cells. One aspect of the fully-malignant-cell concept should be reinterpreted in light of recent data about cancer stem cells: I. Fidler was certainly right to state that not all cells are equally capable to metastasize. The rejection of clonal evolution by some authors prompted by the similarities in gene expression profiles of primary tumors and metastases and the proposal that all cells in the tumor are equally prone to metastasize provides no adequate interpretation of disease progression in cancer. 35,36 Gene expression analysis of Cell Cycle 1795

10 Table 2 Models of cancer progression and tumor dormancy (continued). Model Supporting Data/ Conflicting Data/ Tumor Dormancy Advantages of Model Difficulties of the Model Parallel progression Early metastases (M1 To explain association with tumor size, Base line dormancy: Time model stage at diagnosis) factors from the primary tumor are required from initiation to are initiated years before postulated that stimulate the initiation diagnosis of metastasis primary diagnosis of metastatic growth. (homogeneous). Cellular dormancy: Time from tumor Def.: Tumor cells Is consistent with a cell dissemination until initiation disseminate early after homogeneous 6-year (varies between patients and transformation and growth period of tumors; may be overcome accumulate many genetic metastases. by stimulating factors from and epigenetic alterations primary tumor). at the distant site parallel Disseminated cells can be to the primary tumor. detected at early tumor stages at ectopic sites. Implication: Metastases are mostly derived from Rate of dissemination does early-disseminating not increase with cell cancer cells. population in primary tumor. Genomic changes of disseminated cancer cells resemble early tumor stages. Genomic divergence between metastases and primary tumors can be explained. CUP syndrom can be explained. Multiple metastases are derived from independently disseminated tumor cells from primary lesions consistent with clinical data. pooled mrna is just not the method of choice to address questions of clonality and selection of variant cells. 37 We already noted that only few of the thousands of disseminated cancer cells would grow to metastases. One of the many possible explanations for this fact may be the potential of cancer cells either to self-renew or to differentiate. The concept of cancer stem cells that divide asymmetrically has gained considerable momentum recently because it may explain many aspects of the disease, such as proliferative potential, aberrant differentiation, chemoresistance, migratory behavior, resistance to apoptosis and particularly to anoikis. 38 Migrating cancer stem cells 39 may therefore be the founders of metastasis. The cancer stem cell concept might even provide an explanation for the surprising reduction of migratory cells in advanced cancers where most cancer cells may have differentiated. In addition, it has been noted that critically short telomeres inhibit epithelial stem cell migration. 40 Telomere crisis, which results from telomere shortening and leads to chromosomal aberration detectable by CGH, may therefore be associated with a reduced migratory capacity of genomically advanced tumor cells. In large cancers most likely all tumor cells have passed through telomere crisis and thus might have lost the ability to disseminate. What is tumor dormancy after all? The term dormancy is apparently used for several concepts. In most cases, the longer metastasis free-intervals of small tumors compared to larger tumors consist mostly in the lead-time effect and should not be confused with dormancy. Before disseminated cancer cells start growing cellular dormancy apparently is the destiny of almost all migrated tumor cells. The time until this point is the time required for these early-disseminated cells to acquire all that is necessary for initiation of metastatic growth. In cases with successful initiation, dormancy and growth phases take about six years and this period may be regarded as base line dormancy (see Fig. 2A the example of patient C, where metastasis is initiated just prior to surgical resection of the primary tumor and diagnosed six years later fulfilling the historical definition of clinical dormancy). Dissemination (but not necessarily initiation of metastatic growth!) starts from a small tumor cell population size and might be characteristic for transformed organspecific stem or progenitor cells. The time period from dissemination to initiation certainly depends on the specific genetic and epigenetic changes of the disseminated cells, the genetic background of the patient, the microenvironment in general (including the age of the patient), the cell type being transformed, and additional factors related to primary tumor size that increase the chances of disseminated cancer cells to grow out. There is evidence that primary tumors prepare the metastastic niche for disseminated cancer cells. In one study of a murine cancer model, factors provided by the primary tumor induced bone marrow-derived cells to enter the blood stream and growth factors stimulated production of fibronectin in resident fibroblasts, supporting colonization. 41 Interestingly, this phenomenon was observed already 14 days after tumor implantation, but unfortunately it was not assessed how many tumor cells 1796 Cell Cycle 2006; Vol. 5 Issue 16

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