Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of humancancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell propertyengaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPsdegrade the ECMand, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue Inhibitors of Metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression.

The biology of Kaposi sarcoma is poorly understood because the dominant cell type in Kaposi sarcoma lesions is not known 1-4. We show by gene expression microarrays that neoplastic cells of Kaposi sarcoma are closely related to lymphatic endothelial cells (LECs) and that Kaposi sarcoma herpesvirus (KSHV) 5,6 infects both LECs and blood vascular endothelial cells (BECs) in vitro. The gene expression microarray profiles of infected LECs and BECs show that KSHV induces transcriptional reprogramming of both cell types. The lymphangiogenic molecules VEGF-D and angiopoietin-2 were elevated in the plasma of individuals with acquired immune deficiency syndrome and Kaposi sarcoma. These data show that the gene expression profile of Kaposi sarcoma resembles that of LECs, that KSHV induces a transcriptional drift in both LECs and BECs and that lymphangiogenic molecules are involved in the pathogenesis of Kaposi sarcoma. The cellular origin of the spindle cells of Kaposi sarcoma lesions is poorly defined 3,7. Kaposi sarcoma spindle cells express endothelial cell markers but also have features of other cell lineages, including fibroblasts, macrophages and smooth muscle cells 1-3. Kaposi sarcoma could be a tumor originating from LECs, as spindle cells ubiquitously express VEGFR-3 and podoplanin and stain with the antibody D2-40 recognizing LECs 4,8. But these markers can also be expressed on angiogenic blood vessels, or on other cell types 9. Furthermore, some BEC markers (e.g., CD34) are expressed in all Kaposi sarcoma spindle cells 1. KSHV is the infectious cause of Kaposi sarcoma 5,6. In vitro, KSHV can infect both micro-and macrovascular endothelial cells, and these cells are useful to study the role of KSHV in the pathogenesis of Kaposi sarcoma 10-12 .

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An increased dependency on glycolysis for ATP production is considered to be a hallmark of tumor cells. Whether this increase in glycolytic activity is due mainly to inherent metabolic alterations or to the hypoxic microenvironment remains controversial. Here we have transformed human adult mesenchymal stem cells (MSC) using genetic alterations as described for differentiated cells. Our data suggest that MSC require disruption of the same pathways as have been shown for differentiated cells to confer a fully transformed phenotype. Furthermore, we found that MSC are more glycolytic than primary human fibroblasts and, in contrast to differentiated cells, do not depend on increased aerobic glycolysis for ATP production during transformation. These data indicate that aerobic glycolysis (the Warburg effect) is not an intrinsic component of the transformation of adult stem cells, and that oncogenic adaptation to bioenergetic requirements, in some circumstances, may also rely on increases in oxidative phosphorylation. We did find, however, a reversible increase in the transcription of glycolytic enzymes in tumors generated by transformed MSC, indicating this is a secondary phenomenon resulting from adaptation of the tumor to its microenvironment. adult stem cells ͉ glycolysis ͉ Warburg effect

Summary Swe1 (Saccharomyces WEE1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) in the N-domain of Hsp90. Phosphorylation is cell cycle-associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Non-phosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific post-translational modification of a unique subcellular pool of the chaperone, and they provide a novel strategy to increase the cellular potency of Hsp90 inhibitors.

LIM domains-containing protein 1 (LIMD1) is encoded at chromosome 3p21.3, a region commonly deleted in many solid malignancies. However, the function of LIMD1 is unknown. Here we show that LIMD1 specifically interacts with retinoblastoma protein (pRB), inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. LIMD1 blocks tumor growth in vitro and in vivo and is down-regulated in the majority of human lung cancer samples tested. Our data indicate that LIMD1 is a tumor-suppressor gene, the protein product of which functionally interacts with pRB and the loss of which promotes lung carcinogenesis.lung cancer ͉ retinoblastoma

Summary The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone Heat Shock Protein 90 (Hsp90). Hsp90 function is coupled to ATP binding and hydrolysis, and requires a series of conformational changes that are regulated by co-chaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least understood Hsp90 PTMs. Here we show that asymmetric SUMOylation of a conserved lysine residue in the N-domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the ATPase activating co-chaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N-domain SUMOylation and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.

Kaposi's sarcoma (KS) is caused by Kaposi's sarcomaassociated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection upregulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation.