Morphologic Instability and Cancer Invasion

Abstract

Purpose: A solidt umor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen andce ll nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia andac idosis, and may result in spatially heterogeneous cell proliferation and migration.Here,we formulate the hypothesis that through thesemechanisms,microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue. Experimental Design:We usedc omputer simulations and in vitro experiments. Results:We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen andn utrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A properly working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen andn utrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promotemorphologic instability, leading to invasive patterns even under conditions inwhich the overall tumor mass shrinks. Conclusions:We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy inmultiple clinical trials.We propose that antiangiogenic strategies will be more consistently successful when aimedat ‘‘normalizing’’ the vasculature andw hen combinedw ith therapies that increase cell adhesion so that morphologic instability is suppresseda nd compact, noninvasive tumormorphologies are enforced

Nonlinear Modeling and Simulation of Tumor Growth

“…This can negate the positive effects of anti-angiogenic therapy and lead to recurrence and metastasis. This result is consistent with the findings of [55], who suggested that combining anti-angiogenic therapy with adhesion therapy may counteract the negative problems associated with tumor fragmentation in the nutrient-poor regime.…”

“…Conversely, we found that increasing nutrient levels leads to greater morphological stability and increased tumor compactness, thereby rendering some tumors more resectable. These results support the contention [55] that treatments that seek to normalize tumor vasculature (by selectively "pruning" weak blood vessels with targeted anti-angiogenic therapy) may stabilize tumor morphology by providing increased access to nutrient. Since such treatments may also increase the accessibility to chemotherapeutic agents [105,188], our results provide additional support for the use of targeted anti-angiogenic therapy as adjuvant to chemotherapy and resection.…”

“…(Note that the tumor is continuing to grow.) This provides additional support in 3-D for the hypothesis put forth by [59,55,56] based on 2-D simulations that morphologic instability allows an additional pathway for tumor invasion that does not require an additional nutrient source such as would be provided from a newly developing vasculature through angiogenesis.…”

“…Within this nutrient-poor growth regime, decreasing microenvironmental mobility (by increasing noncancerous cell-cell and cell-ECM adhesion or increasing ECM rigidity) decreases extent of fragmentation and slows invasion into surrounding tissue, but does not completely prevent hypoxia-induced morphological instability. (Unstable tumor morphologies in the nutrient-poor regime have been observed by [10] and [55].) An invasive, fingering morphology was found in cases of growth into nutrient-rich, low-mobility microenvironments.…”

“…As in [59], Zheng et al found that low-nutrient (e.g., hypoxic) conditions could lead to morphological instability. Their work served as a building block for recent studies of the effect of chemotherapy on tumor growth by Sinek et al (2004) [188] and for studies of morphological instability and invasion by Cristini et al, (2005) [55] and Frieboes et al (2006) [74]. Hogea et al (2006) [97] have also begun exploring tumor growth and angiogenesis using a level set method coupled with a continuum model of angiogenesis.…”