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Diversity of Dynamics and Morphologies of Invasive Solid Tumors
Complex tumor-host interactions can significantly affect the growth dynamics
and morphologies of progressing neoplasms. The growth of a confined solid tumor
induces mechanical pressure and deformation of the surrounding
microenvironment, which in turn influences tumor growth. In this paper, we
generalize a recently developed cellular automaton model for invasive tumor
growth in heterogeneous microenvironments [Y. Jiao and S. Torquato, PLoS
Comput. Biol. 7, e1002314 (2011)] by incorporating the effects of pressure.
Specifically, we explicitly model the pressure exerted on the growing tumor due
to the deformation of the microenvironment and its effect on the local
tumor-host interface instability. Both noninvasive-proliferative growth and
invasive growth with individual cells that detach themselves from the primary
tumor and migrate into the surrounding microenvironment are investigated. We
find that while noninvasive tumors growing in "soft" homogeneous
microenvironments develop almost isotropic shapes, both high pressure and host
heterogeneity can strongly enhance malignant behavior, leading to finger-like
protrusions of the tumor surface. Moreover, we show that individual invasive
cells of an invasive tumor degrade the local extracellular matrix at the
tumor-host interface, which diminishes the fingering growth of the primary
tumor. The implications of our results for cancer diagnosis, prognosis and
therapy are discussed.Comment: 21 pages, 5 figures, invited article for the special issue "Physics
of Cancer" in AIP Advances, in pres
New molecular mediators in tumor angiogenesis
Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition
Geometrical approach to tumor growth
Tumor growth has a number of features in common with a physical process known
as molecular beam epitaxy. Both growth processes are characterized by the
constraint of growth development to the body border, and surface diffusion of
cells/particles at the growing edge. However, tumor growth implies an
approximate spherical symmetry that makes necessary a geometrical treatment of
the growth equations. The basic model was introduced in a former article [C.
Escudero, Phys. Rev. E 73, 020902(R) (2006)], and in the present work we extend
our analysis and try to shed light on the possible geometrical principles that
drive tumor growth. We present two-dimensional models that reproduce the
experimental observations, and analyse the unexplored three-dimensional case,
for which new conclusions on tumor growth are derived
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Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.
PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches
Interactions of asbestos-activated macrophages with an experimental fibrosarcoma
Supernatants from in vivo asbestos-activated macrophages failed to show any cytostatic activity against a syngeneic fibrosarcoma cell line in vitro. UICC chrysotile-induced peritoneal exudate cells also failed to demonstrate any growth inhibitory effect on the same cells in Winn assays of tumor growth. Mixing UICC crocidolite with inoculated tumor cells resulted in a dose-dependent inhibition of tumor growth; this could, however, be explained by a direct cytostatic effect on the tumor cells of high doses of crocidolite, which was observed in vitro
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