Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as ‘occult cancer’. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use. “We find ourselves at the present time in the era of molecular biology, and we are perhaps unduly influenced by the genetic code as the dominant principle in biology. Perhaps, in a decade or two from now, the dominant principle may shift to another plane, which in turn will influence our speculations about tumour causation.”1. —Isaac Berenblum

Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I.

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of ''field cancerization'' and ''cancer field effect,'' concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. ' 2006 Wiley-Liss, Inc.Key words: telomere loss; allelic imbalance; genomic instability; cancer field effect; breast cancer Genomic instability is an important factor in the progression of human cancers. [1][2][3][4] One mechanism that underlies genomic instability is loss of telomere function. [5][6][7] Telomeres are nucleoprotein complexes located at the ends of eukaryotic chromosomes. Telomeres in human somatic cells are composed of 1,000 to 2,000 tandemly repeated copies of the hexanucleotide DNA sequence, TTAGGG. 8 Numerous telomere binding proteins are associated with these repeat regions and are important for telomere maintenance. 9,10 Telomeres stabilize chromosome ends and prevent them from being recognized by the cell as DNA double-strand breaks, thereby preventing degradation and recombination. 11 However, telomeres can be critically shortened, and thereby become dysfunctional, by several mechanisms, including incomplete replication of the lagging strand during DNA synthesis, 12 loss or alterations of telomere-binding proteins involved in telomere maintenance, 13 and oxidative stress leading to DNA damage. 14 Alternatively, telomere loss may be compensated for by recombination 15,16 or, as seen in the majority of human cancers, by the enzyme telomerase. 17,18 Telomeres in tumors are frequently shorter than in the matched adjacent normal tissues, presumably reflecting their extensive replicative histories. [19][20][21] The cause-and-effect relation between dysfunctional telomeres and genomic instability implies that shortened telomeres are also associated with altered gene expression. The latter is a primary source of p...

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Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.galectin-1 | sialic acid | mammary gland | breast cancer | glycobiology T ransmission of information between neighboring cells and their tissue microenvironment is essential for organ morphogenesis and homeostasis. The process of transmission can be spatially separated into an extracellular component, which includes cell-ECM adhesion and soluble ligand binding, and an intracellular component, encompassing phosphorylation networks and transcription programs. This strict division is spanned by transmembrane proteins that relay molecular and mechanical cues through both outside-in and inside-out mechanisms. Recently, a growing number of proteins with distinct functions inside and outside cells have been recognized to subvert this conventional mode of cellular communication via alternative secretion (1). Noncanonically secreted proteins can potentially integrate intracellular and extracellular information, in effect influencing tissue specificity and organogenesis (2).Galectin-1 (Gal-1), a soluble lectin, lacks a signal peptide but is secreted to the extracellular environment through unconventional transport. Outside the cell, Gal-1 interacts with glycoconjugates, modulating their surface organization and mediating cell-cell and cell-ECM contact (3-5). Within the cell, Gal-1 is found in the cytosol and nucleus, where it has been proposed to play roles in signaling (6) and transcription (7,8), respectively, that are unrelated to glycan-binding activity (9)...