| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Review |
1 All authors: Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287.
Received March 28, 2000;
accepted after revision April 3, 2001.
Presented at the annual meeting of the Radiological Society of North
America, Chicago, November 1999.
Introduction
 Top Introduction Basic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
Jain [1,2,3,4] at the Massachusetts General Hospital, Boston, has been a leader in this field, and many of the concepts and experimental results presented in this review are adapted from his work. As Jain has pointed out, potential barriers to systemic drug delivery exist at every step, including transporting the drug via the blood to the targeted tumor, crossing the vessel wall within the tumor, and crossing the tumor interstitium to reach the targeted cells. These barriers to drug delivery apply to all systemic therapies, including conventional chemotherapy, immune mediators, WBC, and even oxygen, which enhances the free-radical—related toxicity of radiation therapy. In this review, we outline the basic composition of solid tumors, describe the process known as angiogenesis by which tumors form abnormal vessels, and briefly discuss the major barriers inherent in solid tumors as a direct result of their composition and abnormal vasculature. Finally, we outline important potential implications of these barriers for imaging and imaging-guided therapy.
Basic Composition of Solid Tumors
|
TopIntroductionBasic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
Solid tumors have three basic components [1] (Fig. 1). The cancer cells themselves are usually the largest component, often accounting for more than 50% of the tumor volume. Malignant tumors are proliferations of genetically abnormal cells. Many new, genetically engineered agents target the unique molecules and genes expressed by tumor cells. It is hoped that such agents will act as "magic bullets" that selectively seek out and destroy tumor cells without the systemic toxicity associated with conventional therapies.
|
Blood vessels account for 1-10% of the tumor volume in tumors large enough to form their own vessels. A tumor initially grows within normal tissue using existing host vasculature. This stage of tumor development is called the prevascular phase. Once the tumor grows larger than a few cubic millimeters, it outstrips the host blood supply and must induce the formation of new vessels by a process called angiogenesis. These new vessels form through the sprouting of capillaries from already existing microvessels. The resulting tumor vessels are abnormal in both structure and function [1, 3].
The remainder of the tumor is composed of a collagen-rich matrix—the interstitium—that is more abundant in tumor tissues than in normal host tissues [1]. The interstitium is the connective tissue matrix that provides both structural and nutritional support for the tumor as it grows. The interstitium also contains inflammatory cells, fibroblasts, and other accessory cells and enzymes that can affect the delivery of drugs to the tumor. Growth of the interstitium is induced by tumor cells in a process similar to wound healing. The tumor vasculature and interstitium are sometimes considered together as the tumor stroma, a requirement if a tumor is to grow larger than 1-2 mm. Unlike normal host tissue, a tumor does not form lymphatics [1].
|
TopIntroductionBasic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
Angiogenesis involves several steps [10] (Fig. 2A,2B,2C,2D). Initially, host capillaries dilate and develop increased permeability. These "leaky" vessels allow fibrin to escape from the blood pool into the interstitium, creating an extracellular matrix that facilitates cell growth. Proteases and collagenases break down capillary basement membranes, allowing endothelial cells to proliferate across the disrupted membrane into the interstitium. Finally, the new endothelial cells canalize into a functional vessel.
|
|
|
|
Tumor cells stimulate angiogenesis directly through the release of cytokines and growth factors [10]. The new, stimulated endothelial cells can, in turn, create a synergistic or positive feedback effect by stimulating further tumor growth. Other host cells such as macrophages and fibroblasts also express growth factors and angiogenic factors. A large and growing list of factors have been shown to have angiogenic and antiangiogenic properties [10]. The two most well-known and widely studied angiogenic factors are vascular permeability—vascular endothelial growth factor and basic fibroblast growth factor. Both agents are expressed by a number of tumor types, and they have been shown to have synergistic activities.
Barriers to Molecular Delivery in Solid Tumors
|
TopIntroductionBasic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
Barrier 1: Transport of Molecule via Blood to Tumor
The vascular system of solid tumors resulting from angiogenesis is
disorganized in both structure and function
[1,2,3,4,
11,12,13].
Tumor angiogenesis produces abnormal vessels with increased branching and
tortuosity. The blood in the tumor vasculature may have increased viscosity
compared with that in normal tissues because of the leaky tumor vessels. A
small tumor tends to have a uniform blood vessel distribution; however, as a
tumor grows larger, a more heterogeneous distribution of vascular supply
develops in different regions of the tumor
(Fig. 3). The advancing front
or periphery of the tumor tends to be hypervascular, whereas the tumor center
is hypovascular and often necrotic. The result is poor drug delivery to the
central, poorly vascularized areas in large solid tumors. In addition, the
tortuosity of the vessels produced by tumor angiogenesis coupled with
increased blood viscosity in tumors hinders bloodborne drug delivery even in
the more vascularized regions.
|
Barrier 2: Crossing the Vessel Wall
Molecules of substances such as drugs and contrast agents cross the vessel
wall by two main mechanisms: diffusion and convection
[1,2,3,4].
Diffusion is molecular transport that is driven by concentration gradients,
and it is the dominant transport mechanism for small molecules such as those
in conventional chemotherapy drugs and oxygen. Large molecules move slowly by
diffusion. Convection is transport that is driven by pressure gradients. It is
less dependent on molecular size and is the dominant transport mechanism for
large molecules such those of genetically engineered therapies involving
proteins and gene vectors. Both mechanisms play some role in all cases of
transport through the vessel wall, but one or the other may play a dominant
role depending on molecular size and existing pressure and concentration
gradients. Similar concepts apply to liposomes and other particles.
Tumors initially grow in normal tissue using existing host vasculature. Host lymphatics drain fluid from interstitium, keeping interstitial pressures low. As the tumor grows larger, tumor angiogenesis produces abnormal (leaky) new vessels that have more permeability and larger pore size, increasing inflow of fluid into the interstitium [14]. These leaky vessels are also less permselective than normal vessels and therefore allow larger molecules such as plasma proteins to cross the vessel wall [14,15,16], increasing interstitial oncotic pressure. The tumor eventually outgrows host lymphatics and cannot create its own. Therefore, effective outflow of interstitial fluid is reduced. The result is increased interstitial pressure in the tumor [17,18,19]. The interstitial pressure is uniformly elevated throughout tumor interstitium except at the periphery of the tumor, where the pressure rapidly drops to 0 d, the normal value in nontumor interstitium (Fig. 4A,4B). The increased interstitial pressure reduces the pressure gradient between the intra- and extravascular spaces, hindering the transport of large molecules across vessel walls by convection. Larger tumors tend to have higher interstitial pressures than smaller tumors.
|
|
Barrier 3: Crossing the Interstitium to the Targeted Cancer
Cells
Once a molecule has crossed the vessel wall into the tumor, it must travel
through the interstitium to the targeted tumor cells. Because the interstitial
pressure is nearly uniform throughout solid tumors
[17,18,19],
convection does not contribute significantly to molecular transport in the
interstitium of solid tumors. Instead, molecules move mainly by diffusion.
Small molecules travel relatively rapidly by diffusion; large molecules travel
slowly (Fig. 5). For example,
Jain [3] pointed out that a
large molecule such as a monoclonal antibody (approximately 150,000 d) could
take months to reach a uniform concentration across a 1-cm tumor by diffusion.
The only part of the tumor with enough interstitial pressure gradient to
induce convection is at the tumor periphery, where a steep pressure gradient
drives transport of fluid (and drug or contrast agents molecules) out of the
tumor. There are other barriers in the interstitium as well
(Fig. 5). Genetically
engineered molecules such as antibodies can bind to the tumor interstitium
[20,
21], further hindering
transport. Enzymes in the interstitium actively degrade some drug and biologic
molecules [1]. In addition, the
acidic environment caused by hypoxia and lactic acid production in
hypovascular areas of tumors distant from vessels
[22,
23] can inactivate some
drugs.
|
Implications for Imaging and Imaging-Guided Therapy
Large biologic molecules such as antibodies targeted at solid tumors are
fighting an uphill battle. Although the biologic specificity provided by such
molecules is attractive both from an imaging and a therapeutic perspective,
the barriers that solid tumors present to the delivery of such molecules via a
systemic route are formidable. The somewhat disappointing clinical results
obtained with monoclonal antibodies (Fig.
6) used for nuclear medicine imaging can, at least in part, be
directly attributed to such barriers
[24]. Successful strategies
for using biologically specific imaging agents must take into account the
important effect of molecule size. Larger molecules move much more slowly by
diffusion, which is the dominant means of molecular transport across the
vessel wall and through the interstitium in solid tumors with increased
interstitial pressure.
|
Tumor angiogenesis creates the tumor vessels that are essential for the delivery of drugs and contrast agents to solid tumors. An important area of current research is the development of imaging techniques that can help in accurately detecting and quantifying tumor angiogenesis. At the most basic and qualitative level, early, rapid tumor enhancement is directly related to angiogenesis [25, 26]. Established techniques exist for measuring tissue perfusion, vascular permeability, and vascular volume using contrast-enhanced CT and MR imaging and nuclear medicine. Preliminary results have also shown the usefulness of power Doppler sonography for quantifying tumor blood vessels [27]. Specificity remains the main stumbling block. Considerable overlap exists between the enhancement observed in tumors and that observed in benign processes such as inflammation and granulation of tissue that can also result in increased blood flow and vascular permeability [28]. In a number of tumor types, increased microvessel density has been shown to correlate with poorer prognoses, including higher rates of metastases and poorer rates of patient survival [9, 10]. Microvascular density has important implications for the delivery of molecules for diagnosis of and therapy for solid tumors. In breast cancer, for example, enhancement on MR imaging has been shown to be proportional to microvascular density [26]. Thus, it is expected that accurate imaging techniques for quantifying angiogenesis may provide important prognostic information and help to direct therapy.
Changes in enhancement related to angiogenesis and relative hypovascularity in the central portions of tumors compared with adjacent normal tissues provide increased lesion conspicuity that allows improved detection of tumors in organs such as the liver [29]. Contrast enhancement and increased signal on T2-weighted MR images are the imaging correlates of the increased microvascular density and vascular permeability that occurs with angiogenesis. Current techniques for CT and MR imaging of hepatocellular carcinoma use arterial-phase contrast-enhanced imaging (Fig. 7) to aid in detecting the early enhancement associated with tumor angiogenesis. Because tumor vessels are more prone to leaking substances with large molecules than are vessels in normal tissues [14], macromolecular contrast agents may prove more specific for tumors because they may cross tumor vessels but not normal vessels [30]. Also, results of initial studies have suggested that increased parenchymal enhancement on CT scans—possibly related to neovascularity in tiny tumor deposits—may be used to predict the future appearance of macroscopic hepatic metastases [31]. These are examples of how tumor-related angiogenesis can improve the detection of small malignant foci.
|
Endothelial cells in the immediate vicinity of a tumor express receptors for angiogenic factors, but those distant from the tumor do not [10]. This observation provides the basis for the development of a new class of tumor-specific contrast agents and therapies. Agents that target receptors on endothelial cells do not face many of the barriers related to crossing the vessel wall and interstitium. Therapies aimed at tumor angiogenesis can be antiangiogenesis therapies, which inhibit new vessel formation, and antineovascular strategies, which target existing tumor microvasculature [10]. A number of antiangiogenic factors has been identified, including angiostatin and antibodies to angiogenic factors [10]. The most common antineovascular methods use selective antibodies to target the tumor endothelium [10]. The antineovascular approach theoretically has an advantage in that it attacks existing tumor vasculature, whereas the antiangiogenic approach only prevents the formation of new tumor vasculature. Antiangiogenic agents should be selective because most host tissues do not normally have rapid endothelial proliferation.
The fact that it is much harder for a blood-borne agent to reach therapeutic levels in a large tumor than in a microscopic tumor deposit provides rational for imaging-guided ablation of metastases. Clinical studies performed with surgical resection of liver metastases from colorectal cancer have shown that complete treatment of gross metastatic foci can indeed prolong patient survival. Resection of isolated liver metastases can be curative, with 5-year survival rate ranging from 25% to 39% compared with a median survival of only 12 months with unresectable liver involvement [32]. Unfortunately, only 10-20% of patients with colorectal liver metastases are resectable [32]. These statistics suggest that local treatment of metastases can be extremely effective, and, at the same time, point to the need for effective methods for treating patients with unresectable liver metastases. Imaging-guided techniques for tumor ablation, such as radiofrequency ablation, cryoablation, ethanol ablation, and transcatheter chemoembolization, directly address this need and do so with lower morbidity and mortality rates than standard surgical resection procedures.
Large (>1 cm) liver metastases that can be seen on imaging studies are often accompanied by more widespread disease. However, large tumors are the most difficult to treat with systemic therapies because they tend to have the highest interstitial pressures. Large, biologic molecules are particularly difficult to deliver to large tumors; they move very slowly by diffusion. The combined use of ablation to treat large tumor foci, which have large barriers to the delivery of systemic agents, and systemic therapies to treat micrometastases, which are not visible on imaging, exploits the complementary strengths of both techniques. Given the barriers to anti-cancer therapies, it is not surprising that single-treatment modalities and agents have had limited success in the treatment of solid tumors. Successes using combined treatments of chemotherapy, radiation, and surgery in entities such as esophageal cancer [33] have shown that exploiting the complementary strengths of various forms of therapy can substantially improve treatment success.
The neovascularity in solid tumors can hinder thermal ablation. The hypervascularity often present at the margin of the tumor can act as a heat sink that limits the heating or cooling of tissue used in radiofrequency ablation and cryoablation, respectively. Because of the distance from the ablation probe, treatment margins are likely to undergo the smallest total temperature change and the slowest rate of temperature change, both of which can reduce tumor-cell kill [34]. The dense neovascularity often present at the front of solid tumors may exacerbate these problems and further limit tumor-cell kill. Initial clinical results of liver tumor ablation have been mixed, with some authors reporting low local recurrence rates, similar to those obtained with surgery [35], and others reporting local recurrence rates as high as 44% [36]. Experimental results with cryoablation of VX2 carcinoma in the rabbit liver suggest that some microvessels remain intact inside the gross ablation margin and protect adjacent tumor cells from lethal conditions by a heat-sink effect. These vessels then provide a blood supply to any surviving cells [28]. Similarly, in radiofrequency ablation of the liver, modulation of blood flow has been shown to alter the coagulation achieved with a standard radiofrequency application [37].
Tumor neovascularity can be exploited by imaging-guided therapies. Transcatheter chemoembolization of hepatocellular carcinoma and hypervascular metastases makes use of the high flow directed toward tumors to carry embolic agents and local chemotherapy agents to targeted tumors with relative selectivity. Hypervascularity related to normal healing after tumor ablation might provide a similar opportunity. A dense rind of granulation tissue is seen at the margins of ablated liver tissue at approximately 1 week after cryoablation [28]. Angiogenesis is as central to wound healing, as it is to solid tumor growth. In fact, the marked similarities between tumor stroma and granulation tissue [15] raise the question of whether the dense neovascularity associated with healing at the margins of ablated areas may actually facilitate the regrowth of any remaining viable tumor cells [28]. Nevertheless, the neovascularity of granulation tissue may convert the margin of an otherwise hypovascular tumor such as a colorectal metastasis to a hypervascular environment that could potentially be cleaned up with transcatheter chemoembolization or hepatic arterial infusion chemotherapy [38].
Direct infusion of drugs or genetically engineered molecules into the tumor interstitium overcomes barriers 1 and 2. It also allows high local concentrations of a drug in the tumor without the side effects associated with high systemic concentrations. Imaging-guided, minimally invasive approaches are well suited to direct interstitial delivery of anticancer agents. Enzymatic degradations of the interstitial matrix using agents such as hyaluronidase may improve molecular transport in the interstitium and improve the effectiveness of locally delivered anticancer agents [39, 40]. Diffusion-weighted MR imaging could be used to assess barriers posed by the tumor interstitium and to evaluate the efficacy of techniques aimed at improving transport across the interstitium. Local drug delivery has been shown to be effective in specific applications such as brain tumors [41] and may have a role in the treatment of other solid tumors. Precise delivery of such therapies into the tumor via a percutaneous approach using imaging guidance in a way that ensures adequate treatment throughout a solid tumor volume represents an important area of radiologic research.
Techniques that reduce interstitial pressure in solid tumors would be expected to enhance the delivery of systemic therapies or contrast agents. Radiation therapy has been shown to reduce interstitial pressure [42] and increase the blood flow [43] in solid tumors. These effects may be responsible for the increased uptake of antibodies and other macromolecules observed in solid tumors after radiation [44]. In human colon adenocarcinoma grown in severe combined immunodeficient mice, modulation of tumor microvascular pressure by infusion of angiotensin II enhances transvascular fluid filtration and can lead to a 40% increase in specific antibody uptake by the targeted tumor [45]. Similarly, reducing molecular binding and enzymatic inactivation of such molecules should improve delivery of drugs. Complex computer-based models have been developed that allow optimization of molecular delivery parameters and scaling of animal data so that results in humans may be predicted [46]. Such computer models, coupled with the experimental use of animal models, should provide valuable insight in this area and speed the transfer of new strategies to the clinical arena.
|
TopIntroductionBasic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
|
TopIntroductionBasic Composition of Solid...Tumor AngiogenesisBarriers to Molecular Delivery...ConclusionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging PNAS, September 25, 2007; 104(39): 15549 - 15554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Fleischer, K. J. Niermann, E. F. Donnelly, T. E. Yankeelov, K. M. Canniff, D. E. Hallahan, and M. E. Rothenberg Sonographic Depiction of Microvessel Perfusion: Principles and Potential J. Ultrasound Med., November 1, 2004; 23(11): 1499 - 1506. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
