@article {336, title = {Forcing form and function: biomechanical regulation of tumor evolution.}, journal = {Trends Cell Biol}, volume = {21}, year = {2011}, month = {2011 Jan}, pages = {47-56}, abstract = {

Cancer cells exist in a constantly evolving tissue microenvironment of diverse cell types within a proteinaceous extracellular matrix. As tumors evolve, the physical forces within this complex microenvironment change, with pleiotropic effects on both cell- and tissue-level behaviors. Recent work suggests that these biomechanical factors direct tissue development and modulate tissue homeostasis, and, when altered, crucially influence tumor evolution. In this review, we discuss the biomechanical regulation of cell and tissue homeostasis from the molecular, cellular and tissue levels, including how modifications of this physical dialogue could contribute to cancer etiology. Because of the broad impact of biomechanical factors on cell and tissue functions, an understanding of tumor evolution from the biomechanical perspective should improve risk assessment, clinical diagnosis and the efficacy of cancer treatment.

}, keywords = {Animals, Biomechanical Phenomena, Cell Transformation, Neoplastic, Extracellular Matrix, Humans, Neoplasms, Signal Transduction}, issn = {1879-3088}, doi = {10.1016/j.tcb.2010.08.015}, author = {Yu, Hongmei and Mouw, Janna Kay and Weaver, Valerie M} } @article {301, title = {In situ force mapping of mammary gland transformation.}, journal = {Integr Biol (Camb)}, volume = {3}, year = {2011}, month = {2011 Sep}, pages = {910-21}, abstract = {

Tumor progression is characterized by an incremental stiffening of the tissue. The importance of tissue rigidity to cancer is appreciated, yet the contribution of specific tissue elements to tumor stiffening and their physiological significance remains unclear. We performed high-resolution atomic force microscopy indentation in live and snap-frozen fluorescently labeled mammary tissues to explore the origin of the tissue stiffening associated with mammary tumor development in PyMT mice. The tumor epithelium, the tumor-associated vasculature and the extracellular matrix all contributed to mammary gland stiffening as it transitioned from normal to invasive carcinoma. Consistent with the concept that extracellular matrix stiffness modifies cell tension, we found that isolated transformed mammary epithelial cells were intrinsically stiffer than their normal counterparts but that the malignant epithelium in situ was far stiffer than isolated breast tumor cells. Moreover, using an in situ vitrification approach, we determined that the extracellular matrix adjacent to the epithelium progressively stiffened as tissue evolved from normal through benign to an invasive state. Importantly, we also noted that there was significant mechanical heterogeneity within the transformed tissue both in the epithelium and the tumor-associated neovasculature. The vascular bed within the tumor core was substantially stiffer than the large patent vessels at the invasive front that are surrounded by the stiffest extracellular matrix. These findings clarify the contribution of individual mammary gland tissue elements to the altered biomechanical landscape of cancerous tissues and emphasize the importance of studying cancer cell evolution under conditions that preserve native interactions.

}, keywords = {Animals, Bioengineering, Biomechanical Phenomena, Biophysical Phenomena, Cell Transformation, Neoplastic, Extracellular Matrix, Female, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Microscopy, Atomic Force, Neoplasm Invasiveness, Retroviridae Infections, Tensile Strength, Tumor Virus Infections, Vitrification}, issn = {1757-9708}, doi = {10.1039/c1ib00043h}, author = {Lopez, Jose I and Kang, Inkyung and You, Weon-Kyoo and McDonald, Donald M and Weaver, Valerie M} } @article {391, title = {Mechanics, malignancy, and metastasis: the force journey of a tumor cell.}, journal = {Cancer Metastasis Rev}, volume = {28}, year = {2009}, month = {2009 Jun}, pages = {113-27}, abstract = {

A cell undergoes many genetic and epigenetic changes as it transitions to malignancy. Malignant transformation is also accompanied by a progressive loss of tissue homeostasis and perturbations in tissue architecture that ultimately culminates in tumor cell invasion into the parenchyma and metastasis to distant organ sites. Increasingly, cancer biologists have begun to recognize that a critical component of this transformation journey involves marked alterations in the mechanical phenotype of the cell and its surrounding microenvironment. These mechanical differences include modifications in cell and tissue structure, adaptive force-induced changes in the environment, altered processing of micromechanical cues encoded in the extracellular matrix (ECM), and cell-directed remodeling of the extracellular stroma. Here, we review critical steps in this \"force journey,\" including mechanical contributions to tissue dysplasia, invasion of the ECM, and metastasis. We discuss the biophysical basis of this force journey and present recent advances in the measurement of cellular mechanical properties in vitro and in vivo. We end by describing examples of molecular mechanisms through which tumor cells sense, process and respond to mechanical forces in their environment. While our understanding of the mechanical components of tumor growth, survival and motility remains in its infancy, considerable work has already yielded valuable insight into the molecular basis of force-dependent tumor pathophysiology, which offers new directions in cancer chemotherapeutics.

}, keywords = {Animals, Biophysics, Cell Transformation, Neoplastic, Epigenesis, Genetic, Extracellular Matrix, Focal Adhesion Protein-Tyrosine Kinases, Humans, Lasers, Microscopy, Atomic Force, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, rho-Associated Kinases, Stress, Mechanical}, issn = {1573-7233}, doi = {10.1007/s10555-008-9173-4}, author = {Kumar, Sanjay and Weaver, Valerie M} } @article {386, title = {A tense situation: forcing tumour progression.}, journal = {Nat Rev Cancer}, volume = {9}, year = {2009}, month = {2009 Feb}, pages = {108-22}, abstract = {

Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed \&$\#$39;mechanoreciprocity\&$\#$39;. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

}, keywords = {Animals, Cell Transformation, Neoplastic, Cytoskeleton, Disease Progression, Gene Expression, Humans, Mechanotransduction, Cellular, Neoplasms, Neoplastic Processes, Stress, Mechanical}, issn = {1474-1768}, doi = {10.1038/nrc2544}, author = {Butcher, Darci T and Alliston, Tamara and Weaver, Valerie M} } @article {396, title = {Biomechanical regulation of cell orientation and fate.}, journal = {Oncogene}, volume = {27}, year = {2008}, month = {2008 Nov 24}, pages = {6981-93}, abstract = {

Biomechanical regulation of tumor phenotypes have been noted for several decades, yet the function of mechanics in the co-evolution of the tumor epithelium and altered cancer extracellular matrix has not been appreciated until fairly recently. In this review, we examine the dynamic interaction between the developing epithelia and the extracellular matrix, and discuss how similar interactions are exploited by the genetically modified epithelium during tumor progression. We emphasize the process of mechanoreciprocity, which is a phenomenon observed during epithelial transformation, in which tension generated within the extracellular microenvironment induce and cooperate with opposing reactive forces within transformed epithelium to drive tumor progression and metastasis. We highlight the importance of matrix remodeling, and present a new, emerging paradigm that underscores the importance of tissue morphology as a key regulator of epithelial cell invasion and metastasis.

}, keywords = {Animals, Biochemical Processes, Bioreactors, Cell Culture Techniques, Cell Differentiation, Cell Movement, Cell Polarity, Cell Transformation, Neoplastic, Embryonic Development, Epithelial Cells, Humans, Mechanotransduction, Cellular, Models, Biological, Neoplasm Metastasis}, issn = {1476-5594}, doi = {10.1038/onc.2008.348}, author = {Lopez, J I and Mouw, J K and Weaver, V M} } @article {431, title = {Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis.}, journal = {Int J Biochem Cell Biol}, volume = {39}, year = {2007}, month = {2007}, pages = {1987-94}, abstract = {

Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.

}, keywords = {Animals, Cell Lineage, Cell Transformation, Neoplastic, Epithelial Cells, Extracellular Matrix, Female, Humans, Mammary Glands, Human, Neoplasms}, issn = {1357-2725}, doi = {10.1016/j.biocel.2007.06.025}, author = {Kass, Laura and Erler, Janine T and Dembo, Micah and Weaver, Valerie M} } @article {506, title = {The tension mounts: mechanics meets morphogenesis and malignancy.}, journal = {J Mammary Gland Biol Neoplasia}, volume = {9}, year = {2004}, month = {2004 Oct}, pages = {325-42}, abstract = {

The tissue microenvironment regulates mammary gland development and tissue homeostasis through soluble, insoluble and cellular cues that operate within the three dimensional architecture of the gland. Disruption of these critical cues and loss of tissue architecture characterize breast tumors. The developing and lactating mammary gland are also subject to a plethora of tensional forces that shape the morphology of the gland and orchestrate its functionally differentiated state. Moreover, malignant transformation of the breast is associated with dramatic changes in gland tension that include elevated compression forces, high tensional resistance stresses and increased extracellular matrix stiffness. Chronically increased mammary gland tension may influence tumor growth, perturb tissue morphogenesis, facilitate tumor invasion, and alter tumor survival and treatment responsiveness. Because mammary tissue differentiation is compromised by high mechanical force and transformed cells exhibit altered mechanoresponsiveness, malignant transformation of the breast may be functionally linked to perturbed tensional-homeostasis. Accordingly, it will be important to define the role of tensional force in mammary gland development and tumorigenesis. Additionally, it will be critical to identify the key molecular elements regulating tensional-homeostasis of the mammary gland and thereafter to characterize their associated mechanotransduction pathways.

}, keywords = {Animals, Biomechanical Phenomena, Cell Transformation, Neoplastic, Homeostasis, Humans, Morphogenesis, Neoplasms}, issn = {1083-3021}, doi = {10.1007/s10911-004-1404-x}, author = {Paszek, Matthew J and Weaver, Valerie M} } @article {541, title = {Tumour-stromal interactions. Integrins and cell adhesions as modulators of mammary cell survival and transformation.}, journal = {Breast Cancer Res}, volume = {3}, year = {2001}, month = {2001}, pages = {224-9}, abstract = {

Stromal-epithelial interactions modulate mammary epithelial cell (MEC) growth and apoptosis by influencing cell adhesion and tissue organization. Perturbations in the mammary stroma and cell adhesion characterize breast tumors and underlie the altered tissue organization, disrupted tissue homeostasis and enhanced survival phenotype of the disease. Apoptosis resistance likely arises during malignant transformation via genetic and epigenetic modification of cell adhesion pathways induced by a changing tissue microenvironment. Acquisition of adhesion-linked survival networks that enhance MEC viability in the absence of basement membrane interactions probably promote malignant transformation, and may render breast tumors sufficiently resistant to exogenous apoptotic stimuli to generate multidrug resistance.

}, keywords = {Apoptosis, Basement Membrane, Breast Neoplasms, Cell Adhesion Molecules, Cell Communication, Cell Differentiation, Cell Survival, Cell Transformation, Neoplastic, Drug Resistance, Multiple, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Integrins, Stromal Cells}, issn = {1465-5411}, author = {Chrenek, M A and Wong, P and Weaver, V M} }