Activation in transformed cells of normal stem cells' self-renewal pathways might contribute to the survival life cycle of cancer stem cells and promote tumor progression. The BMI-1 oncogene-driven gene expression pathway is essential for the self-renewal of hematopoietic and neural stem cells. We applied a mouse/human comparative translational genomics approach to identify an 11-gene signature that consistently displays a stem cell-resembling expression profile in distant metastatic lesions as revealed by the analysis of metastases and primary tumors from a transgenic mouse model of prostate cancer and cancer patients. To further validate these results, we examined the prognostic power of the 11-gene signature in several independent therapy-outcome sets of clinical samples obtained from 1,153 cancer patients diagnosed with 11 different types of cancer, including 5 epithelial malignancies (prostate, breast, lung, ovarian, and bladder cancers) and 5 nonepithelial malignancies (lymphoma, mesothelioma, medulloblastoma, glioma, and acute myeloid leukemia). Kaplan-Meier analysis demonstrated that a stem cell-like expression profile of the 11-gene signature in primary tumors is a consistent powerful predictor of a short interval to disease recurrence, distant metastasis, and death after therapy in cancer patients diagnosed with 11 distinct types of cancer. These data suggest the presence of a conserved BMI-1-driven pathway, which is similarly engaged in both normal stem cells and a highly malignant subset of human cancers diagnosed in a wide range of organs and uniformly exhibiting a marked propensity toward metastatic dissemination as well as a high probability of unfavorable therapy outcome.

One of the major problems in management of prostate cancer is the lack of reliable genetic markers predicting the clinical course of the disease. We analyzed expression profiles of 12,625 transcripts in prostate tumors from patients with distinct clinical outcomes after therapy as well as metastatic human prostate cancer xenografts in nude mice. We identified small clusters of genes discriminating recurrent versus nonrecurrent disease with 90% and 75% accuracy in two independent cohorts of patients. We examined one group of samples (21 tumors) to discover the recurrence predictor genes and then validated the predictive power of these genes in a different set (79 tumors). Kaplan-Meier analysis demonstrated that recurrence predictor signatures are highly informative (P < 0.0001) in stratification of patients into subgroups with distinct relapse-free survival after therapy. A gene expression–based recurrence predictor algorithm was informative in predicting the outcome in patients with early-stage disease, with either high or low preoperative prostate-specific antigen levels and provided additional value to the outcome prediction based on Gleason sum or multiparameter nomogram. Overall, 88% of patients with recurrence of prostate cancer within 1 year after therapy were correctly classified into the poor-prognosis group. The identified algorithm provides additional predictive value over conventional markers of outcome and appears suitable for stratification of prostate cancer patients at the time of diagnosis into subgroups with distinct survival probability after therapy

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Survival in lymph or blood is an essential prerequisite for metastasis of carcinoma cells to distant organs. Recently, we reported isolation and initial biological characterization of circulating metastatic cells in a fluorescent, orthotopic, metastatic nude-mouse model of human prostate cancer. Here we show that the metastatic human prostate carcinoma cells selected for survival in the circulation have increased resistance to anoikis, which is apoptosis induced by cell detachment. Using gene silencing and gene transfer techniques, we show that increased expression of the apoptosisinhibitory protein XIAP contributes to anoikis resistance of the circulating metastatic human prostate carcinoma cells. We also provide initial preclinical data on the antimetastatic efficacy of recently discovered small-molecule antagonists of XIAP. (Cancer Res 2005; 65(6): 2378-86)

Understanding cellular and molecular mechanisms of tumor metastasis is critically important for the development of new approaches to cancer treatment. One of the rate-limiting steps in metastatic dissemination is the adhesion of circulating cancer cells to the microvascular endothelium (for review, see Ref. 1). Recent experimental evidence identified endotheliumattached blood-born tumor cells as the seeds of secondary tumors (2). In the lung, early metastatic colonies were entirely within the blood vessels, and hematogenous metastases originated from the intravascular proliferation of tumor cells anchored to the endothelia (2). These results underscored the significance of intravascular intercellular adhesion in cancer metastasis.Although there is a substantial body of evidence demonstrating the role of various adhesion molecules in tumor cell adhesion (1, 3), the molecular and cellular mechanisms of cancer cell adhesion are still often modeled after the dynamics of the leukocyte adhesion cascade. Despite the many physical similarities, interaction of leukocytes and circulating malignant cells with the vascular endothelium are likely to be driven by distinct molecular mechanisms. For example, it is well documented that under conditions of shear force, circulating leukocytes participate in a multi-step cascade of sequential adhesion events involving rolling, adhesion, and transmigration across the vascular wall, where rolling is the first and rate-limiting step ultimately required for stable leukocyte adhesion to the endothelial cells (EC) 1 (4). However, in contrast to leukocytes, published data regarding the rolling and adhesion of tumor cells on vascular endothelium suggest a non-leukocyte-like mechanism (5-9). Furthermore, it is also not clear whether this step is required for stable adhesion of tumor cells to the endothelium. Leukocyte rolling is mostly mediated by the interaction of the members of C-type lectin family, selectins, with their cognate carbohydrate ligands (4, 10). Studies from our laboratories (11, 12) as well as other investigators (13) have recently shown that another lectin, galectin-3, plays a key role in initiating the adhesion of human breast and prostate cancer cells to the endothelium by specifically interacting with the cancerassociated carbohydrate, T antigen. However, these studies were carried out under static conditions, and the relevance of galectin-3-T antigen interactions in mediating cancer cell adhesion under conditions of flow has not been investigated.Shear forces have an important influence on cell adhesion and other cellular functions, and malignant cell lines appear to possess different adhesive properties under static and dynamic conditions (14,15). To elucidate the molecular mechanisms of intercellular adhesive interactions relevant to breast cancer metastasis, we examined the adhesive behavior of two human breast carcinoma cell lines exhibiting distinct metastatic po-

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Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.

Expression analysis of 7129 transcripts was carried out in five human prostate cancer cell lines derived from orthotopic xenografts after one to five passages in nude mice and primary cultures of human normal prostate epithelial (NPE) cells. These experiments identified a consensus class of 214 genes (43 up- and 171 downregulated transcripts), expression of which was altered at least twofold in the same direction in all the cell lines relative to NPE cells. To validate the relevance of altered expression behavior of these genes for human prostate cancer, their expression pattern was evaluated in multiple additional experimental and clinical settings. Expression of 170 of these 214 genes (79%) was altered in the same direction in vivo in experimental human prostate tumors in mice. Similarly, the expression of 151 of the 214 genes (71%) was altered in the same direction in M12 cells, a variant of an SV40 large T antigen transformed normal human prostate epithelial cell line selected for increased malignancy in vivo. In clinical samples of human prostate tumors, the changes in transcript expression levels of majority of these genes (85% of downregulated and 76% of upregulated transcripts) are consistent with alterations of their expression pattern in xenograft-derived cancer cell lines. These results imply that the expression pattern of a large class of genes is consistently altered in multiple experimental models and clinical samples of human prostate cancer and underscore the potential relevance of the xenograft models and cell lines derived from them for expression analysis studies relevant to human cancer.