Physical traits of cancer Nia, Hadi T.; Munn, Lance L.; Jain, Rakesh K.
Science,
10/2020, Letnik:
370, Številka:
6516
Journal Article
Recenzirano
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Physical traits of cancer
The biological and physical properties of tumors contribute to their growth and to treatment outcome. Although intense research efforts have helped to delineate cancer ...biology, the physics of cancer has only emerged in relatively recent times as a key area of research. Nia
et al.
reviewed the physical features that are common to tumors and that limit successful treatment: solid stresses, interstitial fluid pressure, stiffness (rigidity), and architecture and organization of tumor constituents. The authors provide a conceptual framework and discuss the origins of these distinct physical traits of cancer and how they enable and synergize with aberrant cancer biology to fuel cancer initiation, progression, immune evasion, and treatment resistance.
Science
, this issue p.
eaaz0868
BACKGROUND
Historically, cancer has been considered a disease of the cell, caused by mutations in genes that control proliferation, differentiation, and death. In recent decades, however, the microenvironment surrounding the cancer cell has gained notoriety as a coconspirator in tumor initiation, progression, immune evasion, and treatment response. As tumors grow, they disrupt the structure and function of the surrounding tissue via physical and biochemical mechanisms. The resulting physical abnormalities affect both cancer cells and their microenvironment and fuel tumorigenesis and treatment resistance. The links between cancer biology and physics have provided opportunities for the discovery of new drugs and treatment strategies.
ADVANCES
Here, we propose four distinct physical cancer traits that capture the biomechanical abnormalities in tumors: (i) elevated solid stress, (ii) elevated interstitial fluid pressure, (iii) increased stiffness and altered material properties, and (iv) altered tissue microarchitecture. Solid stresses are created as proliferating and migrating cells push and stretch solid components of the surrounding tissue. Being distinct from fluid pressure and close to zero in most normal tissues, solid stresses are large enough to compress blood and lymphatic vessels in and around tumors, impairing blood flow and the delivery of oxygen, drugs, and immune cells. Acting at organ, tissue, and cellular levels, solid stresses activate signaling pathways that promote tumorigenesis and invasiveness and induce treatment resistance. Elevated interstitial fluid pressure is caused by leakage of plasma from abnormally permeable tumor blood vessels and insufficient lymphatic drainage. As a result, the interstitial fluid leaks out of the tumor into the peritumor tissue, causing edema and elution of drugs and growth factors and facilitating invasion and metastasis through flow-induced shear stresses. Increased stiffness is caused by matrix deposition and remodeling. Traditionally used as a diagnostic marker, and more recently as a prognostic factor, increased stiffness activates signaling pathways that promote proliferation, invasiveness, and metastasis of cancer cells. Finally, when normal tissue architecture is disrupted by cancer growth and invasion, microarchitecture is altered. Stromal and cancer cells and extracellular matrix adopt new organization. This changes the interactions between an individual cell and its surrounding matrix and cells, which affects signaling pathways associated with invasion and metastasis.
OUTLOOK
The tumor microenvironment is characterized by both biological and physical abnormalities. The growing appreciation of the role of tumor-stromal interactions in cancer has led to seminal discoveries that have resulted in previously unexplored targets and strategies for treatment. Understanding the key principles underlying the origins and consequences of the physical traits of cancer will be critical for improving treatment. Many of the concepts involved are nonintuitive and require deep and broad understanding of both the physical and biological aspects of cancer. Therefore, a rigorous but accessible description of physical cancer traits will assist research into the physical sciences of cancer—a highly multidisciplinary area—and help it remain an active and progressive subfield of cancer research.
Physical traits of cancer.
To provide a comprehensive framework for understanding the links between the physics of cancer and signaling pathways in cancer biology in terms of a small number of underlying principles, we propose four physical traits of cancer that characterize the major physical abnormalities shared by most if not all tumors.
The role of the physical microenvironment in tumor development, progression, metastasis, and treatment is gaining appreciation. The emerging multidisciplinary field of the physical sciences of cancer is now embraced by engineers, physicists, cell biologists, developmental biologists, tumor biologists, and oncologists attempting to understand how physical parameters and processes affect cancer progression and treatment. Discoveries in this field are starting to be translated into new therapeutic strategies for cancer. In this Review, we propose four physical traits of tumors that contribute to tumor progression and treatment resistance: (i) elevated solid stresses (compression and tension), (ii) elevated interstitial fluid pressure, (iii) altered material properties (for example, increased tissue stiffness, which historically has been used to detect cancer by palpation), and (iv) altered physical microarchitecture. After defining these physical traits, we discuss their causes, consequences, and how they complement the biological hallmarks of cancer.
Cancer and inflammation Munn, Lance L
Wiley interdisciplinary reviews. Systems biology and medicine,
March/April 2017, Letnik:
9, Številka:
2
Journal Article
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The relationship between inflammation and cancer has been recognized since the 17
century,
and we now know much about the cells, cytokines and physiological processes that are central to both ...inflammation and cancer.
Chronic inflammation can induce certain cancers,
and solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination.
,
Consequently, inflammatory pathways have been targeted in attempts to control cancer.
Inflammation is a central aspect of the innate immune system's response to tissue damage or infection, and also facilitates the recruitment of circulating cells and antibodies of the adaptive immune response to the tissue. Components of the innate immune response carry out a robust, but sometimes overly-conservative response, sacrificing specificity for the sake of preservation. Thus, when innate immunity goes awry, it can have profound implications. How the innate and adaptive immune systems cooperate to neutralize pathogens and repair damaged tissues is still an area of intense investigation. Further, how these systems can respond to cancer, which arises from normal 'self' cells that undergo an oncogenic transformation, has profound implications for cancer therapy. Recently, immunotherapies that activate adaptive immunity have shown unprecedented promise in the clinic, producing durable responses and dramatic increases in survival rate in patients with advanced stage melanoma.
Consequently, the relationship between cancer and inflammation has now returned to the forefront of clinical oncology. WIREs Syst Biol Med 2017, 9:e1370. doi: 10.1002/wsbm.1370 For further resources related to this article, please visit the WIREs website.
Fluid forces control endothelial sprouting Song, Jonathan W.; Munn, Lance L.
Proceedings of the National Academy of Sciences - PNAS,
09/2011, Letnik:
108, Številka:
37
Journal Article
Recenzirano
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During angiogenesis, endothelial cells (ECs) from intact blood vessels quickly infiltrate avascular regions via vascular sprouting. This process is fundamental to many normal and pathological ...processes such as wound healing and tumor growth, but its initiation and control are poorly understood. Vascular endothelial cell growth factor (VEGF) can promote vessel dilation and angiogenic sprouting, but given the complex nature of vascular morphogenesis, additional signals are likely necessary to determine, for example, which vessel segments sprout, which dilate, and which remain quiescent. Fluid forces exerted by blood and plasma are prime candidates that might codirect these processes, but it is not known whether VEGF cooperates with mechanical fluid forces to mediate angiogenesis. Using a microfluidic tissue analog of angiogenic sprouting, we found that fluid shear stress, such as exerted by flowing blood, attenuates EC sprouting in a nitric oxide-dependent manner and that interstitial flow, such as produced by extravasating plasma, directs endothelial morphogenesis and sprout formation. Furthermore, positive VEGF gradients initiated sprouting but negative gradients inhibited sprouting, promoting instead sheet-like migration analogous to vessel dilation. These results suggest that ECs integrate signals from fluid forces and local VEGF gradients to achieve such varied goals as vessel dilation and sprouting.
Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects ...cancer cell phenotype, or the molecular pathways involved.
We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.
Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.
Physical forces have a crucial role in tumor progression and cancer treatment. The application of principles of engineering and physical sciences to oncology has provided powerful insights into the ...mechanisms by which these forces affect tumor progression and confer resistance to delivery and efficacy of molecular, nano-, cellular, and immuno-medicines. Here, we discuss the mechanics of the solid and fluid components of a tumor, with a focus on how they impede the transport of therapeutic agents and create an abnormal tumor microenvironment (TME) that fuels tumor progression and treatment resistance. We also present strategies to reengineer the TME by normalizing the tumor vasculature and the extracellular matrix (ECM) to improve cancer treatment. Finally, we summarize various mathematical models that have provided insights into the physical barriers to cancer treatment and revealed new strategies to overcome these barriers.
Improving vascular function provides opportunities to enhance immunotherapy
Immunotherapy with immune checkpoint blockers (ICBs) has revolutionized cancer treatment. Unfortunately, ICB therapy ...usually benefits <15% of patients and causes immune-related adverse events in a substantial number of patients. Another immunotherapy—engineered chimeric antigen receptor (CAR) T cells that specifically target tumor-associated antigens—has transformed the treatment of multiple hematological cancers and exhibited therapeutic potential in solid tumors. Emerging data show that the function of blood vessels associated with tumors is critical in the response to these immunotherapies (
1
,
2
).
Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic ...immune cells to tumors and also results in hypoxia—a hallmark of the abnormal tumor microenvironment (TME)—that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechanotherapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we have developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules, and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy, and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy, and thus increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy.
Diffusive transport of macromolecules and nanoparticles in charged fibrous media is of interest in many biological applications, including drug delivery and separation processes. Experimental ...findings have shown that diffusion can be significantly hindered by electrostatic interactions between the diffusing particle and charged components of the extracellular matrix. The implications, however, have not been analyzed rigorously. Here, we present a mathematical framework to study the effect of charge on the diffusive transport of macromolecules and nanoparticles in the extracellular matrix of biological tissues. The model takes into account steric, hydrodynamic, and electrostatic interactions. We show that when the fiber size is comparable to the Debye length, electrostatic forces between the fibers and the particles result in slowed diffusion. However, as the fiber diameter increases the repulsive forces become less important. Our results explain the experimental observations that neutral particles diffuse faster than charged particles. Taken together, we conclude that optimal particles for delivery to tumors should be initially cationic to target the tumor vessels and then change to neutral charge after exiting the blood vessels.
Advances in our understanding of the structure and function of the lymphatic system have made it possible to identify its role in a variety of disease processes. Because it is involved not only in ...fluid homeostasis but also in immune cell trafficking, the lymphatic system can mediate and ultimately alter immune responses. Our rapidly increasing knowledge of the molecular control of the lymphatic system will inevitably lead to new and effective therapies for patients with lymphatic dysfunction. In this review, we discuss the molecular and physiological control of lymphatic vessel function and explore how the lymphatic system contributes to many disease processes, including cancer and lymphedema.
New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. ...Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a "normalization" of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more "mature" or "normal" phenotype. This "vascular normalization" is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.
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