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Annals of Surgical Oncology 9:610-616 (2002)
© 2002 Society of Surgical Oncology

EDUCATIONAL REVIEW

Role of Angiogenesis in the Development and Growth of Liver Metastasis

Akihiko Takeda, MD, Oliver Stoeltzing, MD, Syed A. Ahmad, MD, Niels Reinmuth, MD, Wenbiao Liu, MD, Alexander Parikh, MD, Fan Fan, BS, Morihisa Akagi, MD and Lee M. Ellis, MD

From the Departments of Cancer Biology (AT, OS, NR, WL, FF, MA, LME) and Surgical Oncology (SAA, AP, LME), The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Lee M. Ellis, MD, Department of Surgical Oncology, Box 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009; Fax: 713-792-4689; E-mail: lellis{at}mdanderson.org

ABSTRACT

Abstract: Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis. Angiogenesis facilitates metastasis formation by providing a mechanism to (1) increase the likelihood of tumor cells entering the blood circulation and (2) provide nutrients and oxygen for growth at the metastatic site. The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy. Vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor are all proangiogenic factors that have been associated with liver metastasis from various primary tumor types. Inhibition of the activity of these factors is a promising therapeutic approach for patients with liver metastases. In addition, inhibition of integrins that mediate endothelial cell survival may also serve as a component of therapeutic regimens for liver metastases. This review focuses on the biology of angiogenesis in liver metastasis formation and growth. Because colorectal carcinoma is the most common tumor to metastasize to the liver, this disease will serve as a paradigm for the study of angiogenesis in liver metastases.

Key Words: Angiogenesis • Liver metastasis • Angiogenic factors • Microenvironment

Folkman and colleagues have established that tumor growth is angiogenesis dependent.1 Rapid exponential growth of tumors does not begin until neovascularization occurs, and tumor growth in organs where blood vessels do not proliferate is limited to the distance that oxygen can diffuse (1–2 mm). Further evidence of the dependence of tumor growth on angiogenesis is the fact that the proliferative index of tumor cells decreases with increasing distance from the nearest capillary blood vessel. In addition, the proliferation of tumor cells is directly proportional to the labeling index of vascular endothelial cells in the tumor. These principles have provided the foundation for our understanding of the biology of tumor angiogenesis.

Angiogenesis is an essential step, not only in the growth of primary tumors but also in the formation of metastases.2 Once tumor cells are established in the organ of metastasis, the metastatic tumor must develop its own blood supply to grow. The purpose of this review is to provide an overview of the biology of the angiogenesis of liver metastasis to identify potential targets for antiangiogenic therapy.

METASTASIS AND ANGIOGENESIS

Metastasis of cancer is a highly selective, nonrandom process consisting of a series of linked, sequential steps favoring the survival of a subpopulation of metastatic cells pre-existing within the primary tumor mass3 (Fig. 1). For a tumor cell to be able to form a metastasis, it must express a complex phenotype that begins with the invasion of the surrounding normal stroma, either by a single tumor cell with increased motility or by groups of cells from the primary tumor. Once the invading cells penetrate the vascular or lymphatic channels, cells may detach and be transported within the circulatory system. Tumor emboli must survive the host’s immune defenses and the turbulence of the circulation, arrest in the capillary bed of compatible organs, extravasate into the organ parenchyma, proliferate, and establish a micrometastasis. Growth of these small tumors requires the development of a vascular supply (angiogenesis) and continuous evasion of host defense cells. Failure to complete one or more steps of the process (e.g., inability to grow in a distant organ’s parenchyma) eliminates the cells. To produce clinically relevant metastases, the successful metastatic cell must therefore exhibit a complex phenotype that is regulated by transient or permanent changes in different genes at the DNA and/or messenger RNA level(s).2,3



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  		FIG. 1. The metastatic cascade. Angiogenesis is critical in the growth of the primary tumor, the release of tumor cells into the circulation, and the growth of tumors at metastatic sites. (Reproduced with permission from Fidler et al. Biology of Cancer Angiogenesis. In: DeVita JR, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 6th Edition. Philadelphia: Lippincott Williams & Wilkins Publishers, 2001:137–47; Copyrighted 2001, Lippincott Williams & Wilkins).

 
An essential step in the metastatic cascade is angiogenesis. Early work in the field of angiogenesis was based on a simple model in which a tumor cell would release a soluble factor that would then bind to an endothelial cell and induce endothelial cell proliferation, leading to neovascularization. Bouck4 refined this model, proposing that angiogenesis is actually the outcome of the balance between stimulatory and inhibitory factors. Further studies demonstrated that the delicate balance of these stimulatory and inhibitory angiogenic factors can be regulated by oncogenes and tumor suppressor genes.5 Pathologic angiogenesis occurs when the effect of stimulatory factors outweighs the effect of inhibitory factors (Table 1). A better understanding of the process of angiogenesis led to the realization that the process involves more than simply endothelial cell proliferation but rather discrete steps in which endothelial cells divide, invade the basement membrane, migrate, and eventually undergo differentiation and capillary tube formation. More recently, Holash and associates6 proposed that newly formed metastases survive by co-opting pre-existing blood vessels within an organ. The metastases then induce neovascularization from these pre-existing blood vessels to support further growth. This theory is especially relevant to liver metastasis because this is the primary site of gastrointestinal cancer metastases.


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  		TABLE 1. Endogenous proangiogenic and antiangiogenic factors
 
LIVER MICROENVIRONMENT AND ANGIOGENESIS

Successful metastasis depends in part on the interaction of favored tumor cells with a compatible milieu provided by a particular organ environment.7 In humans and in experimental rodent systems, numerous examples exist in which malignant tumors metastasize to specific organs.3 The microenvironment of each organ can influence the implantation, invasion, survival, growth, and angiogenesis of tumors. A number of studies have shown that endothelial cells in different organs are phenotypically distinct and express different levels of receptors for specific angiogenic factors.8 In addition, tumors themselves can alter the endothelial cell phenotype independent of the organ of endothelial cell origin. This obviously has important implications for antiangiogenic therapy.

The liver is the most common site of distant metastasis from colorectal cancer for two main reasons. First, the liver filters the venous drainage from the intra-abdominal viscera, including the distal esophagus, stomach, spleen, small bowel, colon, rectum, adrenals, pancreas, gallbladder, and biliary tree. Furthermore, the liver receives 30% of the cardiac output. Thus, the volume of blood filtered by the liver is second only to that filtered by the lungs. Second, physiologically, the liver is occupied by numerous cell types capable of providing a rich milieu for tumor cell growth. Tumor cells that survive the systemic circulation may eventually reach the liver. If the tumor cells express the appropriate phenotype allowing progression through all stages of the metastatic cascade, then the result is a metastasis.

The liver microenvironment consists of not only organ-specific cells, such as hepatocytes, but also endothelial cells, pericytes, inflammatory cells, Kupffer cells, fibroblasts, and the extracellular matrix, all of which provide a favorable milieu for tumor cell implantation and initiation of angiogenesis.9 Angiogenesis of liver metastases progresses stepwise as the metastases enlarge and capillarization of the sinusoidal endothelium around the liver metastases occurs.10,11 In an experimental model of metastatic liver tumors from Lewis lung carcinoma, Paku and Lapis identified two types of angiogenesis in these metastases: a sinusoidal type containing convoluted vessels and lacking a basement membrane and a portal type with a high microvessel density and positive staining for a basement membrane. In the first type, which was the dominant type, tumor cells were located between the hepatocytes and sinusoidal endothelial cells.12 Others have also demonstrated that the sinusoidal endothelial cells eventually comprise the vasculature of metastasis.13

ANGIOGENIC FACTORS RELATED TO LIVER METASTASIS

Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) plays a pivotal role in vasculogenesis and angiogenesis; of all the angiogenic factors identified, VEGF is the one most frequently associated with tumor progression and metastasis.14 VEGF is expressed as at least five isoforms that produce alternative splicing of messenger RNA: VEGF-121, VEGF-145, VEGF-165, VEGF-189, and VEGF-206.15 Preliminary evidence suggests that overexpression of various isoforms of VEGF may have differential effects on tumor angiogenesis.16

Tokunaga et al.16 specifically studied the expression of various VEGF isoforms in 61 colon cancer specimens. Patients whose tumors expressed the three isoforms VEGF-121, VEGF-165, and VEGF-189 had a greater incidence of liver metastasis and a poorer prognosis than did patients whose tumors expressed only VEGF-121 or VEGF-121 and VEGF-165. Relatively high VEGF expression was associated with metastasis in colon cancer patients, whereas low VEGF expression was associated with a favorable prognosis. This is similar to findings from our own laboratory17 (Fig. 2), as well as others (Table 2). Therefore, the expression of VEGF may be useful as a prognostic marker in colon cancers.



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  		FIG. 2. Effect of vascular endothelial growth factor (VEGF) expression by the primary tumor on metastasis formation and survival. (A) Primary colon cancer specimens were immunohistochemically stained for VEGF. As the expression of VEGF increased in the primary tumor, the probability of metastasis increased. (B) VEGF expression was assessed in the primary tumors of node-negative colon cancer patients. Patients with high VEGF expression in their primary tumor had a lower survival rate. (Reproduced with permission from Takahashi et al. Cancer Res 1995;55:3964–8; Copyrighted 1995, Cancer Research, and Takahashi et al., Arch Surg 1997;132:541–6; Copyrighted 1997, American Medical Association).

 

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  		TABLE 2. Select studies of angiogenic factors and their role in colon cancer progression and metastasis
 
Receptors for VEGF are expressed predominantly on endothelial cells, although recently VEGF receptors have been found on numerous other cell types, both malignant and nonmalignant. The current nomenclature for the VEGF receptors lists three receptors: VEGF-R1 (Flt-1), VEGF-R2 (KDR/Flk-1), and VEGF-R3 (Flt-4). These tyrosine kinase receptors require dimerization to induce intracellular signaling; they bind to specific ligands as shown in Fig. 3. Different VEGF receptors may mediate distinct functions within the endothelial cells. For example, VEGFR-1 may function in cellular migration, whereas VEGFR-2 may function in induction of permeability and endothelial cell proliferation.



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  		FIG. 3. Vascular endothelial growth factor (VEGF) family members and receptors. PlGF, placenta growth factor.

 
Interleukin-8
The chemokine interleukin-8 (IL-8), originally discovered as a chemotactic factor for leukocytes, has been shown to contribute to human cancer progression through its potential function as a mitogenic, angiogenic, and motogenic factor.28 IL-8 expression is regulated by the tumor microenvironment; tumor hypoxia and acidosis increase expression of IL-8. IL-8 not only may directly stimulate tumor cell proliferation but also may support tumor growth by direct or indirect induction of angiogenesis. In one study, IL-8 expression in vitro directly correlated with the extent of local growth and the development of spontaneous liver metastasis after orthotopic implantation of human pancreatic carcinoma cells into the pancreases of nude mice.29 In a study of colon cancer cell lines, there was a strong correlation between constitutive expression of IL-8 and its receptors, CXCR1 and CXCR2, and increasing metastatic potential.30 In clinical studies, serum levels of IL-8 were significantly higher in colorectal cancer patients with liver metastasis than in those without liver metastasis.31 Overexpression of IL-8 has also been associated with tumor aggressiveness in gastric cancer.32 Thus, IL-8 may contribute to tumor progression and angiogenesis in several gastrointestinal tumor types.

Integrins and Extracellular Matrix
The integrins are a family of cell adhesion receptors, each of which is a heterodimer complex of two transmembrane subunits, {alpha} and ß. Thus far, 16 different {alpha} and eight different ß subunits with 22 different combinations have been identified. Integrins bind to extracellular matrix adhesion proteins. Many studies have demonstrated that integrins, as important transducers of extracellular matrix signals, maintain endothelial cell survival. If the integrins cannot interact with the extracellular matrix, the endothelial cells will no longer receive the survival signal from the extracellular matrix and will rapidly undergo apoptosis.

Integrins are implicated in the development and growth of hepatic metastasis. In 110 resected human gastric cancers, {alpha}2ß1 and {alpha}3ß1 integrins were associated with liver metastasis and found to be independent prognostic factors related to liver metastasis in a multivariate analysis.33 Blocking cell-surface {alpha}vß3 molecules with specific anti-ß3 monoclonal antibodies resulted in significant decreases in the adhesion of highly liver-colonizing H10 cells and significant inhibition of the formation of experimental liver metastases of murine RAW117 large cell lymphoma in the liver.34 Recently, our laboratory demonstrated that the integrin {alpha}5ß1 antagonist ATN-161 in combination with a low-dose continuous infusion of 5-fluorouracil reduced liver metastasis formation and improved survival in a murine colon cancer model.35 In other studies, antagonists to the integrins {alpha}vß3 and {alpha}vß5 have also led to a decrease in colon cancer liver metastasis formation and angiogenesis.36

Platelet-Derived Endothelial Cell Growth Factor
Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase, is another tumor angiogenic factor; in several cancer systems, PD-ECGF has chemotactic activity for endothelial cells in vitro and angiogenic activity in vivo.37 PD-ECGF strongly induces neovascularization in the rat sponge model, and PD-ECGF–transfected breast carcinoma cells exhibit accelerated growth in xenografts in mice.38 In one study, Maeda et al.39 immunostained 120 gastric cancer specimens for PD-ECGF and microvessels and found a significantly higher microvessel density in tumors that expressed PD-ECGF. Moreover, the frequency of liver metastasis was significantly higher in patients with PD-ECGF–positive tumors than in those with PD-ECGF–negative tumors. Studies from our laboratory have shown that PD-ECGF expression in gastric cancer was greater in intestinal-type tumors that metastasize to the liver than in diffuse-type tumors that typically metastasize to the peritoneal cavity.40 Others have shown, in a liver metastasis model using a PD-ECGF–transfected cell line, that a novel inhibitor of PD-ECGF can inhibit liver metastasis formation.41

Thrombospondin-2
Thrombospondin (TSP) is a high-molecular-weight, multifunctional glycoprotein first described as a product of platelets released in response to thrombin activation.42 TSP is synthesized and secreted by fibroblasts, vascular smooth muscle cells, monocytes, and macrophages, as well as neoplastic cells.43 Two of five subtypes of TSP, TSP-1 and TSP-2, have been implicated in the inhibition of angiogenesis. Tokunaga et al.44 investigated the significance of TSP-2 in colon cancer. Among 61 colon cancer specimens, 38 were positive for TSP-2 expression; the incidence of liver metastasis in these patients was much lower than in patients whose tumors did not express TSP-2.

ANGIOGENIC FACTORS AS PROGNOSTIC FACTORS AND THERAPY TARGETS

Antiangiogenic therapy is perhaps the most active field of anticancer research. However, the mechanism of action of many agents being investigated in preclinical and clinical trials is not known. A more effective approach to antiangiogenic therapy might be to target a specific angiogenic factor and to develop therapies to inhibit the activity of this factor. VEGF is one potential target for antiangiogenic therapy. Currently, potential therapies to inhibit VEGF expression include VEGF antibodies or antibodies to its receptors, specific tyrosine kinase inhibitors of the VEGF receptors, VEGF antisense DNA, ribozymes, or soluble VEGF receptors. Preclinical studies with agents that inhibit VEGF activity have demonstrated decreased growth of metastasis, which is associated with a decrease in angiogenesis.45–48 However, it must be recognized that a decrease in growth is, in reality, slowly "progressive disease" by standard oncologic perspectives. Thus, one should not expect antiangiogenic therapy alone to lead to tumor regressions, but a realistic expectation is to anticipate a delayed time-to-progression and improved survival.

It is unlikely that single agent antiangiogenic therapy will be of benefit to patients with established metastatic disease. It is more likely that antiangiogenic therapy will be most efficacious when combined with standard chemotherapeutic regimens, thus targeting the tumor cells in general and the endothelium specifically. There are several phase III clinical trials either completed or in progress examining the effect of chemotherapy with or without anti-VEGF therapy for patients with metastatic colorectal cancer. For a detailed list of current antiangiogenic agents in clinical trials, access the Web site http://www.cancer.gov/clinical_trials./

CONCLUSIONS

Angiogenesis is essential for the growth of primary tumors, the development of metastasis, and the continued growth of liver metastasis. The unique vascular architecture of the liver enables a tumor to acquire adequate nutrients and oxygen through various mechanisms, such as vessel co-option, modification of the existing sinusoidal network, and, eventually, traditional angiogenesis (Fig. 4). Understanding the molecular phenotype of these vascular networks allows appropriate targeting with agents that inhibit the function of ligands or receptors on endothelial cells that mediate the angiogenic process.



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  		FIG. 4. Importance of the angiogenic process in primary and metastatic tumor growth. The process of metastasis is dependent on alterations in the angiogenic phenotype at both the primary site and the organ of metastasis. ECs, endothelial cells; VEGF, vascular endothelial growth factor; PD-ECGF, platelet-derived endothelial cell growth factor; TSP-2, thrombospondin-2.

 

Acknowledgments

Supported in part by the German Dr. Mildred Scheel Stiftung für Krebsforschung, Deutsche Krebshilfe (N.R.), National Institutes of Health Grants T-3209599 (S.A.A., A.P.) and CA74821 (L.M.E.), the Jon and Suzie HallTM Fund for Colon Cancer Research (L.M.E.), and the Gillson Longenbaugh Foundation (L.M.E.). The authors thank Melissa G. Burkett of the Department of Scientific Publications for editorial assistance.

Footnotes

The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy.

Received for publication March 4, 2002. Accepted for publication April 25, 2002.

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J. B. Fleming, G.-L. Shen, S. E. Holloway, M. Davis, and R. A. Brekken
Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras-Directed Therapy
Mol. Cancer Res., July 1, 2005; 3(7): 413 - 423.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. Li, K. Guo, V. W. C. Koh, J. P. Tang, B. Q. Gan, H. Shi, H. X. Li, and Q. Zeng
Generation of PRL-3- and PRL-1-Specific Monoclonal Antibodies as Potential Diagnostic Markers for Cancer Metastases
Clin. Cancer Res., March 15, 2005; 11(6): 2195 - 2204.
[Abstract] [Full Text] [PDF]

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 RadiologyHome page
P. V. Pandharipande, G. A. Krinsky, H. Rusinek, and V. S. Lee
Perfusion Imaging of the Liver: Current Challenges and Future Goals
Radiology, March 1, 2005; 234(3): 661 - 673.
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 Cancer Res.Home page
H.-K. Yu, J.-S. Kim, H.-J. Lee, J.-H. Ahn, S.-K. Lee, S.-W. Hong, and Y. Yoon
Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles
Cancer Res., October 1, 2004; 64(19): 7092 - 7098.
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 Clin. Cancer Res.Home page
C. J. Bruns, G. E. Koehl, M. Guba, M. Yezhelyev, M. Steinbauer, H. Seeliger, A. Schwend, A. Hoehn, K.-W. Jauch, and E. K. Geissler
Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer
Clin. Cancer Res., March 15, 2004; 10(6): 2109 - 2119.
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H. Seeliger, M. Guba, G. E. Koehl, A. Doenecke, M. Steinbauer, C. J. Bruns, C. Wagner, E. Frank, K.-W. Jauch, and E. K. Geissler
Blockage of 2-Deoxy-D-Ribose-Induced Angiogenesis with Rapamycin Counteracts a Thymidine Phosphorylase-Based Escape Mechanism Available for Colon Cancer under 5-Fluorouracil Therapy
Clin. Cancer Res., March 1, 2004; 10(5): 1843 - 1852.
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Q. Zeng, J.-M. Dong, K. Guo, J. Li, H.-X. Tan, V. Koh, C. J. Pallen, E. Manser, and W. Hong
PRL-3 and PRL-1 Promote Cell Migration, Invasion, and Metastasis
Cancer Res., June 1, 2003; 63(11): 2716 - 2722.
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