Journal of Gastrointestinal Surgery

, 12:966

Liver Regeneration and Tumor Stimulation—A Review of Cytokine and Angiogenic Factors

Authors

    • Department of SurgeryUniversity of Melbourne
  • Nadia Harun
    • Department of SurgeryUniversity of Melbourne
  • Theodora Fifis
    • Department of SurgeryUniversity of Melbourne
Article

DOI: 10.1007/s11605-007-0459-6

Cite this article as:
Christophi, C., Harun, N. & Fifis, T. J Gastrointest Surg (2008) 12: 966. doi:10.1007/s11605-007-0459-6

Abstract

Liver resection for metastatic (colorectal carcinoma) tumors is often followed by a significant incidence of tumor recurrence. Cellular and molecular changes resulting from hepatectomy and the subsequent liver regeneration process may influence the kinetics of tumor growth and contribute to recurrence. Clinical and experimental evidence suggests that factors involved in liver regeneration may also stimulate the growth of occult tumors and the reactivation of dormant micrometastases. An understanding of the underlying changes may enable alternative strategies to minimize tumor recurrence and improve patient survival after hepatectomy.

Keywords

Colorectal carcinomaLiver resectionLiver regenerationCytokinesAngiogenesisGrowth factorsTumor recurrence

Introduction

Long-term survival in patients with secondary liver tumors is achieved in selected patients by hepatic resection. Five-year survival rates in patients undergoing liver resection for colorectal cancer liver metastases range from 20% to 40%.1 Despite sophisticated staging techniques and adequate surgical clearance, local and systemic recurrences occur in the remaining patients. Recurrent disease in these patients usually appears within the first 12 to 18 months after resection at both hepatic and extrahepatic sites. Approximately 50% of recurrences occur in the liver only, while 15–20% occur in both hepatic and extrahepatic sites. Approximately 25–30%2 occur in extrahepatic sites only. Timing of the recurrences varies according to the organ involved. In general, extrahepatic recurrences occur later than hepatic recurrences and predominantly in the lung and lymph nodes indicating possible different causative mechanisms. The degree of liver resection is also a significant factor in the patterns of tumor recurrence.

Prognostic factors influencing recurrence after liver resection for colorectal metastases are several. The most significant adverse factors are involved resection margins and the presence of extrahepatic disease. The initial staging of the primary tumor, the number of metastases, timing to recurrence from the primary operation, the degree of differentiation and the presence of specific biological markers are also important prognostic parameters. The presence of angiogenic markers such as a high tumor vessel density and high preoperative serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), epidermal growth factor (EGF), and basic fibroblast growth factor (b-FGF)3,4 indicate a high propensity to tumor recurrence.

There is now accumulating clinical and experimental evidence that suggests specific factors involved in liver regeneration may influence the growth patterns of residual or dormant micrometastases after resection. The site of these micrometastases and sources of future recurrences remain controversial.

This review will assess evidence on the possible role of cytokine and angiogenic factors involved in liver regeneration on tumor recurrence.

Evidence for Recurrence of Metastases After Tumor Resection

Clinical evidence suggests that stimulation of tumor growth may occur after resection of liver tumors.57 Surgical strategies such as portal vein embolization and two-stage hepatectomy involving liver regeneration may also be associated with stimulation of tumor growth. Elias et al. performed studies, which assessed liver regeneration after right portal vain embolization of patients who had undergone hepatic resection. The growth rate of liver metastases exceeded that of the normal liver parenchyma by almost eight times, suggesting that the process of regeneration has significant proliferative effect on tumor cells.8 Kokudo et al. also reported that portal embolization before hepatic resection caused significant enhancement in the growth rate of colorectal cancer (CRC) metastases and poorer disease-free survival in these patients compared to those treated only with hepatic resection.9 Togo et al.10 have reported a high incidence of residual liver and lung metastases after two-stage hepatectomy and the need for protective measures such as chemotherapy during the liver regenerative phases. Adam et al.11 has emphasized the need of adjuvant chemotherapy during portal vein embolization and two-stage hepatectomy to prevent tumor proliferation during the liver regenerative phase. A report by von Schweinitz et al.12 found accelerated residual tumor growth in children with embryonal hepatoblastoma after liver resection compared to untreated patients. The accelerated growth correlated with increased HGF serum levels.

Animal studies have also confirmed that there is stimulation of tumor growth after liver resection. The degree of liver resection is a significant factor in the degree of tumor stimulation and the development of extrahepatic metastases.13 De Jong et al.14 demonstrated that liver regeneration may influence the growth of the remaining micrometastases in the liver by hepatotropic factors. Using rats induced with metastatic colorectal cancer, enhanced growth in the remnant liver after 70% partial hepatectomy was observed. Other studies in hepatectomized rats challenged with tumor cells found that the hepatic metastatic tumors grew faster than in sham hepatectomies.15 There was no difference in the growth rate of extrahepatic metastases between the two groups, suggesting a local paracrine stimulation by factor(s) related to liver regeneration. In a different study by Schindel and Grosfeld,6 both hepatic and extrahepatic metastases grew at a faster rate than those in the sham hepatectomized control rats, suggesting that factors induced by hepatectomy influence both local and distal tumor growth. Our studies have confirmed that 70% hepatic resection was associated with increased peritoneal and lung metastases as well as increased growth of intrahepatic metastases. The increase in growth in liver metastases occurred predominantly in the late phase of liver regeneration rather than the early phase.16 In a study with nude mice, it was found that even minimal liver resection results in a dramatic acceleration of recurring colorectal cancer liver metastases after hepatectomy.17

Studies by Ikeda18 and Slooter et al.13 suggest that the frequency of metastases after hepatectomy is proportional to the extent of resection. Mueller et al.19 using a rat model showed that portal branch ligation is associated with increased expression of genes known to promote tumor growth. Kollmar et al.20 showed that partial hepatectomy significantly increased tumor metastases when compared with nonresected controls or laparoscopy-treated animals and correlated with a significant increase in the expression of the macrophage-inflammatory protein-2 (MIP-2) receptor CXCR-2 on tumor cells and accelerated tumor angiogenesis.

Liver Regeneration After Hepatectomy

Adult hepatocytes are differentiated, metabolically active, and the majority is in the resting (G0) state.21 During liver regeneration, they undergo a “priming” phase to become “proliferatively competent” and move from G0 to G1. After the priming phase, growth factors and other mitogens stimulate cell proliferation, so that they undergo sufficient rounds of mitosis to restore the original mass of the liver.22,23 The molecular trigger to liver proliferation appears to be loss of functional hepatic mass. For example, in experimental partial hepatectomy, removal of one third of the liver evokes a poor proliferative response (only isolated hepatocytes proliferate), whereas two-thirds removal provokes 80% to 90% of hepatocytes to undergo coordinated rounds of mitosis.24 Sensors of such ideal “hepatic functional mass” remain unclear. From gene array and proteomic studies, numerous genes have shown alteration in their expression after hepatectomy.2527 Some of the upregulated genes are absolutely necessary for regeneration to occur,2830 whereas others show degrees of redundancy.28,31

The genes involved in liver regeneration fall into three categories: cytokines, growth factors, and genes with metabolic functions.32 The trigger of the liver regeneration cascade is thought to be the result of shear stress-induced nitric oxide (NO) and prostaglandins (PGs)33,34 after the increase in the blood flow-to-liver mass ratio after liver resection. The initiation trigger is followed by an increase in liver cytokines.35,36 Liver regeneration occurs roughly in three stages (Fig. 1). The first stage is the “priming stage” and occurs during the first few hours after resection. Tumor necrosis factor-alpha (TNF-α) and interleukin- 6 (IL-6) cytokine signaling pathways are the main cytokine activated pathways and their signaling duration is very tightly controlled.25
https://static-content.springer.com/image/art%3A10.1007%2Fs11605-007-0459-6/MediaObjects/11605_2007_459_Fig1_HTML.gif
Figure 1

Molecular and ultrastructural changes during liver regeneration. Signaling through the TNFR, IL-6R, and IGFBP1R receptors prime the hepatic cells to enter mitosis. Signaling through c-Met, EGFR, Flk1, and FGFR promote DNA synthesis and drive proliferation during the proliferative phase. TGF-β and b-FGF through their receptor signaling are responsible for growth termination and ECM synthesis. Metalloproteinases play a pivotal role in ECM degradation, the generation of active growth factors, and signaling molecules from the ECM and cell surfaces. They are also responsible for the degradation or inactivation of these factors when none are required.

Hepatocytes primed through these pathways become responsive to growth factors and enter into the second stage, the proliferative stage. The growth factors and their receptors that dominate this stage have proliferative and cytoprotective functions. The main factors involved are HGF, EGF receptor ligands such as EGF and TGF-α, heparin-binding EGF like growth factor (HB-EGF), amphiregulin,37 growth hormone (GH),38 and insulin growth factor binding protein-1 (IGFBP1).30 The increased metabolic demand on the remaining liver remnant after resection may be the sensor that dictates the extent of replication and also signal the termination onset. Proliferation inhibiting factors such as the transforming growth factor beta (TGF-β) superfamily, which includes TGF-β1, 2, and 3, activins, and inhibins among others, are involved in the termination stage of liver regeneration.3941

During liver regeneration, there is a breakdown and remodeling of the extracellular matrix (ECM)40 as illustrated in Fig. 1. This is accomplished by the metalloproteinases (MPPs) secreted by pericytes in response to HGF stimulation.42 During the proliferation phase, the hepatocytes form avascular clusters. The sinusoids become shorter and more dilated and completely disappear in some areas (Fig. 2b). Stellate and endothelial cells proliferate later than hepatocytes and also form clusters adjacent to the hepatocytes. Some of the stellate cells associated with the hepatocyte clusters become activated and fibroblastic in function (Fig. 2c). In the later stages of regeneration, under the stimulation of TGF-β they secrete ECM components. At this stage, endothelial cells migrate into the hepatocyte clusters initiating the reorganization of the hepatocytes and establishment of microcirculation (Fig. 2c). Angiogenesis during liver regeneration involves ECM remodeling and the upregulation of proangiogenic growth factors such as hypoxia-induced factor-1a (HIF-1α), VEGF, and b-FGF.43,44 New vessels are formed from proliferation and migration of endothelial cells from neighboring vessels and the mobilization and recruitment of endothelial precursor cells (EPC) from the bone marrow.4547 The mobilization of both types of cells is induced by local VEGF production, which is upregulated in liver regeneration.47
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Figure 2

Cellular and ultrastructural changes in liver morphology during liver regeneration. (a) Degradation of ECM proteins and collagen. Release and activation of preformed growth factors and other signaling molecules from cell surfaces or the ECM. Cleavage of cell adherence proteins such as cadherins allows cells to move and proliferate. (b) Upregulation of growth factors. Hepatocytes undergo DNA synthesis and proliferation forming avascular clusters by 48 hours. Proliferation of non-parenchymal cells by 72 hours. Stellate cells form clusters and are often found within the hepatocyte clusters or near endothelial cells. Sinusoids shorten and become more dilated and cannot be seen in some areas. (c) Peak upregulation of pro-angiogenic growth factors VEGF, b-FGF, and TGF β. Synthesis of new ECM components by activated stellate cells. Upregulation of cell adhesion molecules. Adhesion ligands attach to new ECM fibers. Migration of endothelial cells into hepatocyte clusters and reconstruction of new sinusoid vasculature.

Factors in Liver Regeneration that May Influence Tumor Growth and Metastasis

Tumor recurrence after hepatectomy may result from circulating tumor cells or dormant micrometastases. The source of these occult metastases is uncertain. Micrometastases are detectable on histological examination in resected specimens. These may reside in the portal vein, central vein, sinusoids, and the bile duct.48 Minimal residual disease in bone marrow may also be a source of tumor micrometastases49 A number of publications report positive tumor cell circulation after surgery.50 It has been shown, in animal models, that approximately 106 tumor cells per gram of tumor tissue may be shed daily into the systemic circulation.51 New metastases establish in selective tissues that express receptors that are able to recognize specific ligands such as integrin αvβ3 on the circulating tumor cells.52 These ligands must be activated for adhesion53,54 and maybe activated during liver regeneration through proteolytic cleavage of inactive surface ligands by MMPs.

It has been suggested that micrometastases remain dormant because proliferation and apoptosis rates of tumor cells are mutually antagonistic.55,56 Tumor growth requires the balance of growth factors and cytokines in the microenvironment to favor angiogenesis.57 Angiogenic inhibitors such as circulating angiostatin, ECM proteins such as thrombospondin,58 or ECM protein fragments such as endostatin59 are considered responsible for maintaining the dormant state. Major surgery including hepatectomy results in a major influx of angiogenic factors and cytokines that could alter the microenvironment of distant dormant tumor deposits causing their reactivation. In addition, the activation of the coagulation cascade,60 the temporary local and systemic immunosuppression after surgery,61 and the mobilization of EPC and other hematogenic cells have also been shown to enhance tumor metastases.62

The liver ECM breakdown and rebuilding during liver regeneration may be a major source of tumor metastasis, both hepatic and extrahepatic. Tumor cells in micrometastases may become detached and find their way to other hepatic sites or into the blood and lymphatic circulation (Fig. 3).
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Figure 3

Molecular and ultrastructural changes during liver regeneration could promote tumor recurrence. a: Tumor ECM breakdown. Cleaving of cell-cell attachments, activation of cell surface ligands and shedding of cell surface ligands. b: Growth factor signalling may stimulate proliferation in tumor cells. Free tumor cells may escape into new sites or into the circulation. c: Upregulation of VEGF, b-FGF and TGF-β may induce EMT transition in tumor cells. Upregulation of adhesion molecules on tumor cell surface may aid their migration into new intrahepatic sites or into new vessels and the systemic circulation.

ECM breakdown and remodeling at a smaller scale occurs also at the tumor interface. The factors involved (urokinase-type plasminogen activator (uPA), MMPs, HIF-1α, VEGF) are common to those of the liver ECM remodeling during liver regeneration. It has been shown that metastatic epithelial tumors undergo an epithelial to mesenchymal transition (EMT) to become invasive.63 Various stimuli within the tumor microenvironment also promote EMT transition of carcinoma cells. These include growth factors that bind to tyrosine-kinase receptors (TKR), such as b-FGF, EGF, and HGF, members of the TGF-β superfamily and ECM constituents including MPPs.64 These factors are upregulated by hepatectomy and in ECM remodeling and may account for increased metastases after liver resection (Fig. 3).

Growth factors such HGF, EGF, TGF-α, TGF-β, HIF-1α, VEGF, and MPPs have been shown in numerous studies (outlined in detail in the following sections) to be associated with tumor aggressiveness and metastasis. Therefore, additional upregulation of these factors during liver regeneration may enhance the metastatic process.

HGF

Hepatocyte growth factor (HGF) is one of the most important growth factors upregulated during liver regeneration. Expression of HGF increases 6 to 8 hours after partial hepatectomy. It is produced and secreted by stellate cells, sinusoidal endothelial cells, and Kupffer cells and acts in a paracrine manner.65,66 Studies using liver specific HGF receptor (c-Met) knockout mice showed that HGF/c-Met signaling is essential for liver regeneration after hepatectomy.67,68 HGF is a multifunctional factor. In cell culture, it induces strong mitogenic stimulation on hepatocytes and other cell types69,70 and exerts morphogenic, mitogenic, and proangiogenic effects on normal and neoplastic epithelial cells.7173 It has functional roles in angiogenesis, wound healing, and carcinogenesis.74 Tamatani et al.75 reported that addition of exogenous HGF accelerated tumor migration and infiltration and increased MMP activity, suggesting an important role in tumor invasion and progression. HGF stimulates cell motility and the secretion of proteinases, which lyse the tumor basement membrane promoting metastasis.76,77 HGF is occasionally secreted by tumors, stimulating tumor growth in an autocrine manner.78

The HGF receptor belongs to the family of receptors of tyrosine kinases and is encoded by the c-Met protooncogene.7981 HGF through c-Met and Mitogen-activated protein kinase (MAPK) signaling was shown to induce growth, invasion, and metastasis in hepatocellular carcinoma (HCC) tumors,82 and to be involved with high-grade invasive bladder cancer.75 The HGF/c-Met have also been implicated in CRC pathogenesis.83 HGF also cooperates with other receptors such as the insulin growth factor receptor (IGFR) in promoting tumor growth.84

EGFR and its Ligands

The EGFR, a tyrosine kinase receptor of the ErbB family, comprises the second major signaling system, after the HGF/c-Met, in liver regeneration.37 The EGFR belongs to a family of four closely related receptors: EGFR (ErbB-1), HER-2/neu (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4). Ligand binding on the EGFR results in the activation of its tyrosine kinase (TK) activity. It initiates receptor-mediated signal transduction, cell mitogenesis, and cell transformation. EGFR ligands include EGF, TGF-α, amphiregulin, HB-EGF, epiregulin, and cellulin. The binding of these ligands to the receptor results in different function modulation for each of them, ranging from cell motility and proliferation to growth inhibition.37 A number of the EGFR ligands have been shown to be upregulated during liver regeneration (EGF, TGF-α, amphiregulin, and HB-EGF).

The activity of EGFR is abnormally elevated in most human solid tumors85 including CRC86 and human HCC.8789 EGFR overexpression correlates with early tumor recurrence90 and extrahepatic metastasis. The EGFR signaling also induces VEGF upregulation and the induction of angiogenesis.9193 Cetuximab or gefitinib therapy (EGFR inhibitors), in a colon carcinoma model, results in a decrease of VEGF, b-FGF, and TGF-α expression and a reduction in microvessel count.94,95 Another EGFR family ligand upregulated in liver regeneration, HB-EGF, binds to ErbB1 and ErbB2 receptors. It plays a major role in angiogenesis by stimulating ErbB receptor phosphorylation and migration of smooth muscle cells (SMCs).96,97 TGF-α, another EGFR ligand is also upregulated in liver regeneration and is associated with adverse predictors of survival when upregulated in tumor.98

VEGF

Angiogenic growth factors such as VEGF that promote new vasculature formation from preexisting blood vessels are increased during liver regeneration. Most solid tumors overexpress and secrete VEGF.99 It is also secreted by infiltrating immune cells such as monocytes.100,101 Solid tumors are generally hypoxic, resulting in HIF-1α upregulation, which in turn induces angiogenic factors such as VEGF production.102 VEGF is also induced through EGFR and c-Met signaling.97,103 VEGF also plays a role in vasculogenesis by recruiting endothelial progenitor cells from the bone marrow for endothelial vessel formation. Tumors producing high levels of VEGF are associated with increased tumor vascularity, metastasis, chemoresistance, and poor prognosis.104

VEGF has several other associated actions, which enhance tumor angiogenesis and metastatic potential, including the upregulation of the VEGF receptor FLK-1 in tumor cells.105 VEGF also induces the synthesis of a stroma-derived factor (SDF-1) that recruits circulating cells from the periphery to the tumor site where they differentiate into cancer-associated fibroblasts (CAFs). These produce b-FGF and many other factors associated with ECM remodeling, angiogenesis, and cancer-cell EMT.64 Basic FGF induces endothelial cell proliferation, migration, and capillary tube formation.106

TGF-β

Transforming growth factor beta (TGF-β), upregulated in liver regeneration, enhances angiogenesis and metastases by promoting accumulation of ECM glycoproteins and adhesion proteins.107 Serum TGF-β levels correlate with the development of liver metastasis after potentially curative hepatic resection.4,108 Changes in expression and mutations in the genes for TGF-β, the TGF-β receptors, and the SMAD proteins also correlate with metastatic cancers of the colon, liver, and pancreas.107 Loss of the TGF-β receptors, TGFβR2 and TGFβR1, occurs often in human liver cancer, disrupting the TGF-β signaling pathway.109,110 Similar loss of these receptors has been reported in preneoplastic and malignant cells from rats, mice, and humans, indicating that loss of the antiproliferative TGF-β signaling results in tumorogenesis.111

IGF-I and IGFR

Insulin growth factor I (IGF-I) has not been shown to be upregulated during hepatectomy by gene arrays,25 and no function has been attributed to it in the regeneration process. However, liver regeneration after hepatectomy is disrupted in male mice that do not express the IGFR in the liver.112 It is possible that IGF-I is modulated as a byproduct of growth hormone upregulation.38 GH is upregulated during liver regeneration and it has been shown to be important for the regeneration process. It is the primary regulator of IGF-I synthesis and secretion in hepatocytes. IGF-I in turn regulates GH secretion through a negative feedback loop.113 IGF-I levels in circulation are modulated by the IGF-binding proteins (IGFBPs) and only 5% of IGF-I circulates unbound.114,115 The majority of IGF-I in the body is manufactured by the liver116. Although it is not clear if IGF-I has a role in liver regeneration, there is able evidence that IGF-I and its tyrosine kinase receptor play important roles in the development and progression of a variety of human cancers including CRC.117 IGF-I induces CRC proliferation, and high IGF-R expressing tumors colonize the liver more readily than low IGF-IR expressing tumors.118 This may be the reason that the majority of CRC metastases are found in the liver. Epidemiological studies have established a correlation between circulating levels of IGF-I and IGFBP-3 and the relative risk for developing colon, breast, prostate, and lung cancer.119,120 High levels of IGF-I and low levels of IGFBP-3 are independently associated with an increased risk of colorectal cancer. Warren et al.121 showed that IGF-I induces VEGF expression in cultured colorectal carcinoma cells. Wu et al.117 also demonstrated VEGF upregulation in tumors by IGF-I addition. Similar to HGF/c-Met, IGF-I/IGFR signaling is known to induce tumor cell migration, invasion, and angiogenesis by stimulating endothelial cell VEGF expression122 and promoting endothelial cell migration.123 Using plasmid-mediated IGF-I therapy, Rabinovsky et al.124 demonstrated increased expression of VEGF and activation of the VEGF receptors FLK-1 (VEGFR-2) and FLT-1 (VEGFR-1). FLK-1 receptor signaling induces endothelial cell proliferation and increases permeability, whereas FLT-1 receptor is implicated in vascular remodeling.125

IGF-I and HGF have been shown to function as co-mitogens in a rat hepatoma cell line126. In addition, Bauer et al.84 demonstrated a tyrosine kinase receptor cooperation between IGFR and c-Met in human CRC. IGF-I appears to be an upstream regulator of the angiogenic cascade. Even if there is no increase in IGF-I growth factor during liver regeneration, the increase of many other tumor promoting factors that have been shown to cooperate in IGF-I/IGFR signaling suggests that IGF-I is an important contributor to accelerated tumor growth and metastatic activity associated with hepatectomy.

MMPs

The role of MMPs is to maintain homeostasis in the extracellular environment. In liver regeneration, they play central roles in promoting growth factor upregulation or activation, and in the breakdown and remodeling of the ECM.40 There are several classes of MMPs, and the biological roles of the majority have not been fully elucidated. MMPs are part of an extensive “protease web” where individual members may also be substrates of other proteases, releasing activated ligands or inhibitors in many signaling pathways.127 Several studies have linked MMPs with numerous types and stages of cancer. They have been implicated in the base membrane alterations leading to tumor metastasis.128,129 Overexpression of particular MMPs has been correlated with tumor progression, and mouse transgenic models overexpressing MMPs support this finding.130 In addition to ECM degradation, MMPs promote tumor progression by modulating the generation and active states of key molecules in various signaling pathways including growth factors and chemokines.127

Clinical Perspectives

Over 50% of patients who undergo resection for colorectal cancer liver metastases will ultimately have recurrent disease in the liver and/or extrahepatic sites. The major adjunct to surgery has been systemic chemotherapy in the neoadjuvant or postoperative situation. Several studies have now confirmed that conventional combination systemic chemotherapy associated with potential curative liver resection has been associated with increased survival rates.131,132 The major areas of concern with the use of chemotherapy have been compromised liver function (steatohepatitis, sinusoidal obstructive syndromes), coagulation disorders, and impaired wound healing. In addition, the regenerative ability of the liver may be compromised, leading to limited surgical options.133 Portal vein embolization and two-stage hepatectomy are used in these situations.

There is now accumulating evidence and strong theoretical considerations that the process of liver regeneration after liver resection stimulates tumor recurrence. The specific pathways, including upregulated growth factors and signaling molecules responsible for tumor stimulation and recurrence, remain undefined. Our own evidence suggests that the late phase of liver regeneration is the key process where this occurs. This would suggest that growth factors and cytokines involved in angiogenesis and ECM remodeling are the key processes in liver regeneration involved in tumor growth and metastases.

Selective targeting of these processes in the late phase of liver regeneration may be beneficial in reducing tumor recurrence, without compromising the early phase of liver regeneration.

There are now several trials at various stages of completion, with therapeutic agents targeting these processes. (Table 1 includes a representative list of such studies.)
Table 1

Cancer Therapies Targeting Angiogenesis and Metastasis Promoting Factors

Target

Inhibitor

Reported Clinical Effects

Clinical Stage

Reference

VEGF-A

mAb Bevacizumab (Avastin)

Survival benefit, disease stabilization, partial regression

FDA approval for metastatic CRC in combination with CT

137

mAb HuMV833

Some clinical activity

Phase I

140

VEGF-A, PDGF

VEGF trap (soluble hybrid VEGFR-1–2 decoy)

Significant radiographic improvement in one patient

Phase I/ II

141

VEGFR-2

mAb 2C3

Inhibits tumor growth and lymphangiogenesis,

Preclinical

142,143

VEGFR-1, -2

SM TKI AZD2171

Partial regression

Phase I

144

VEGFR-1, -2, -3

SM TKI GW786034

Partial regression, disease stabilization

Phase II

145

SM TKI vatalinib PTK787

Significant clinical effect in a subgroup of patients with high LDH levels

Phase III

137,146

VEGFR-1, -2, PDGFR

SM TKI SU11248 (sunitunib)

Partial regression, complete response

FDA approval for metastatic RCC and GIST

144

Some problems with bleeding

VEGFR-1, -2, bFGFR

SM TKI CP-547632

No additional clinical benefit in combination with CT

Phase I/ II

147

VEGFR-1, -2, -3, PDGFR, c-kit, Raf

SM TKI Bay 43-9006 sorafenib

Prolongs progression-free survival

FDA approved monotherapy metastatic RCC

148

PDGFR,c-kit, Abl

SM TKI Imatinib (STI-571)

Significant improvement in survival

FDA approval for treatment of CML and GIST.

149,150

VEGFR-1, -2, -3, EGFR

SM TKI ZD6474

Prologed progression-free survival

Phase II

151

SM TKI AEE788

Significant reduction of tumor growth and metastasis

Preclinical

 

EGFR, bFGFR, FGFR

SM TKI SU6668

Not effective

Phase I

152

EGFR

SM TKI AG1478

Inhibits EGFR activity

preclinical

153

SM erlotinib (OSI-774)

Significant improvement in median survivalnon-small cell lung cancer.

FDA approval for metastatic lung and pancreatic cancers

154

SM Gefitinib

Significant improvement in median survival in non-small cell lung cancer: selected patients

Phase I/II

155

MAb Cetuximab

Promising as monotherapy or in combination with cytotoxic treatment for CRC

FDA approval for metastatic CRC

156

MAb panitumumab

Improved progression free survival

FDA approval for metastatic CRC

157

ErB2

SM TKI AG879

Inhibits tumor in combination with AG1478

Preclinical

158

EGFR, ErB2

SM TKI GW572016

Inhibits tumor xenografts

Preclinical

159

IGF-R

SM NVP-AEW541

Suppression of tumor growth and metastasis

Preclinical

160

IGF-I, IGF-II

Neutralizing mAbs

Significant tumor growth inhibition and longer survival.

Preclinical

161

MMP-2, 3, 9

SM Tanomastat (BAY 12-9566)

No clinical benefit

Phase III

162

MMP-1, 2, 8, 9, 13

Metastat (CMT-3,Col-3)

No clinical benefit

Phase II/III

163

MMP-2, 3, 9, 13, 14 collagenase III

Prinomastat (AG3340)

Discontinued because of adverse complications

Phase II

164

MMP-1, 2, 3, 7, 9, 12

Marimastat (BB-2516)

No benefit

Phase III

165

Broad spectrum MMPs

Rebimastat (BMS-275291)

No improvement, toxic

Phase II/III

166

Angiogenesis

Endostatin combined with radiotherapy

Blocks tumor revascularization in mouse xenografts. No significant tumor regression in cancer patients

Preclinical, Phase II

167,168

Angiostatin

High disease control

Phase II

169

Endothelial cells

EMD-121974 Blocks an endothelial integrin

Tumor and endothelial cell apoptosis not reach significance

Phase II

170

TNP-470 Fumagillin analogue inhibits endothelial cell proliferation

Some clinical benefit. Not effective in colonic carcinoma

Phase I, Preclinical

171,172

αvβ3 integrin

MAb Vitaxin MEDI-523

Limited efficacy

Phase I/II

173

MAb Abergrin MEDI-522

Well tolerated, some clinical activity

Phase I/II

174

αvβ3 and αvβ5integrin

Cilengitide (EMD 121974)

Well tolerated. Tumor and endothelial cell apoptosis did not reach significance

Phase I/II

170

TGF-β

Neutralizing pan-TGF-β mAb

Inhibits metastases when used with other anticancer treatments

Preclinical

175

TGF-β1, TGFβ2 antisense oligonucleotides

Increased progression free time

Phase I/II

176,177

TGF-βRII

Dominant negative receptor (DNRII)

Inhibits tumor. Prolongs survival

Preclinical

178

Soluble domain of TGF-b

Inhibits tumor growth

Preclinical

179

TGF-βRI

SM drugs : SB-505124, SD-208, LY580276

Inhibits tumor growth

Phase I

180

COX-2

SM drug Rofecoxib

Increases levels of endostatin

Phase II/III

181

MIF

Antisense-MIF

Inhibition of tumor growth and metastasis

Preclinical

182

UPAR

uPA peptide antagonist

Clinical activity

Phase I

183

Mabs

Inhibition of tumor xenografts

Preclinical

184

HIF-1α

Antisense HIF-1a oligonucleotide

Significant tumor growth delays or total tumor suppression

Preclinical

185

SM inhibitor PX-478

Significant antitumor activity tumor xenografts

Preclinical

186

HGF

Anti-HGF mAbs

Inhibition of tumor xenografts

Preclinical

184

NK4 (HGF-antagonist)

Inhibits tumor growth, invasion, metastasis and angiogenesis.

Preclinical

187

c-met

c-met small-interfering RNA adenovirus

Downregulation of c-Met. Inhibition of tumor in mouse model

Preclinical

188

mAb=monoclonal antibody, TKI=tyrosine kinase inhibitor, GIST Gastrointestinal stromal tumor, CT=chemotherapy, LDH=lactate dehydrogenase, MIF=macrophage migration inhibitory factor, SM=small molecule, CML=chronic myeloid leukemia, PDGF(R)=platelet-derived growth factor receptor, RCC=renal cell carcinoma

A number of monoclonal antibodies such as bevacizumab, cetuximab, panitumumab, trastuzumab, and small-molecule tyrosine kinase inhibitors, ZD-1839, OSI-774/CP358774, Sorafenib (Bay 439006) Sunitinib (SU11248), STI-571, have FDA approval for cancer treatments, including CRC (Table 1). Angiogenesis has been specifically targeted through VEGF and its receptors. This treatment is thought to be tumor specific as angiogenesis does not occur in adult tissues with the exception of wound healing, ischemia, menstruation, and pregnancy.134 Recent studies, however, indicate that inhibition of VEGF signaling could lead to vascular disturbances in normal tissues and even regression of normal blood vessels.135 Wound healing complications increased from 3.4% to 13% in patients receiving bevacizumab when surgery was performed within 60 days after the last treatment.136 As bevacizumab has a relatively long half life, hepatectomy for tumor downstaging should not be performed for at least 28 days.136 In advanced CRC disease, bevacizumab in combination with other chemotherapies137 has shown significant improvement in overall survival.138 Antiangiogenic drugs in general, however, including bevacizumab, have not proven beneficial as monotherapies in the clinical situation. In advanced tumors, angiogenesis is under the influence of several factors in addition to VEGF,139 which may account for the limited efficacy of anti-VEGF treatments.

Antiangiogenic treatment to prevent recurrence after potentially curative hepatectomy requires further evaluation. A multitargeting inhibitor such as Sorafenib, administered orally, in combination with conventional chemotherapy, may prove to be the most efficacious. The timing of administration of these agents is uncertain and needs investigation.

Conclusion

Tumor recurrence after hepatectomy for liver tumors is a significant clinical problem resulting in long-term mortality. Strategies for the removal of liver tumors have focused on aggressive surgical resection to achieve clear margins, including techniques such as portal vein embolization and two-stage hepatectomy. Accumulating clinical and experimental evidence suggests that factors involved in liver regeneration may stimulate residual micrometastases. A clear understanding of the underlying processes may allow adjuvant therapies to be used at specific time points after resection to minimize the risk of recurrent disease.

Acknowledgment

Financial support for this project was provided by the Austin Health Medical Research Foundation.

Copyright information

© The Society for Surgery of the Alimentary Tract 2007