Effect of non-alcoholic liver disease on recurrence rate and liver regeneration after liver resection for colorectal liver metastases

Original Article


Effect of non-alcoholic liver disease on recurrence rate and liver regeneration after liver resection for colorectal liver metastases


N.W. Molla, MBBS MSc*a, M.M. Hassanain, MBBS PhD*§a, Z. Fadel, MD MSc*, L.M. Boucher, MD PhD, A. Madkhali, MBBS*§, R.M. Altahan, MBBS*, E.A. Alrijraji, MBBS*, E.B. Simoneau, MD*, H. Alamri, MBBS*§, A. Salman, MS*, Z. Gao, MD PhD, P.P. Metrakos, MD CM*


doi: https://doi.org/10.3747/co.24.3133


ABSTRACT

Background

Resection of metastases is the only potential cure for patients with liver metastasis from colorectal cancer (crc-lm). But despite an improved overall 5-year survival, the recurrence rate is still as high as 60%. Non-alcoholic fatty liver disease (nafld) can decrease the liver’s capacity to regenerate after resection and might also affect cancer recurrence, potentially by elevating transforming growth factor β, levels of specific metalloproteinases, and oxidative stress. The objective of the present work was to determine the effect of the histologic features of nafld on cancer recurrence and liver regeneration.

Methods

This retrospective analysis considered 60 patients who underwent an R0 hepatectomy for crc-lm. Volumetric analysis of the liver was calculated using axial view, portovenous phase, 2.5 mm thickness, multiphasic computed tomography images taken before and after surgery. The histologic features of nafld (steatosis, inflammation, and ballooning) were scored using the nafld activity score, and the degree of fibrosis was determined.

Results

The hepatic recurrence rate was 38.33%. Median overall survival duration was 56 months. Median disease-free survival duration was 14 months, and median hepatic disease-free survival duration was 56 months. Multivariate analysis revealed significant correlations of hepatic disease-free survival with hepatocyte ballooning (p = 0.0009), lesion diameter (p = 0.014), and synchronous disease (p = 0.006). Univariate and multivariate analyses did not reveal any correlation with degree of steatosis or recurrence rate.

Conclusions

This study reveals an important potential negative effect of hepatocyte ballooning on hepatic disease-free survival.

KEYWORDS: Non-alcoholic fatty liver disease, nafld, crc liver metastases, liver regeneration, liver volumetrics, liver metastasis recurrence

INTRODUCTION

Colorectal cancer is the 3rd leading cause of cancer-related death, most commonly from uncontrolled metastasis1. The liver is the most common site of metastasis, with the median overall survival for patients with metastatic disease to the liver being 6–12 months in the absence of treatment24. Of all colorectal cancer patients, 50% will develop liver metastasis during the course of their disease5, and 15%–20% will present with synchronous liver metastasis5. The treatment of colorectal cancer liver metastasis (crc-lm) is chemotherapy; in a small fraction of patients in whom it is possible to remove all disease (15%–20%), liver resection (R0) is also indicated6. The 5-year overall survival for patients who undergo an R0 resection for crc-lm is 25%–44%7,8. Of patients who undergo a liver resection for crc-lm, 60% experience recurrence9.

As a result of the high recurrence rate after curative liver resection, many investigators have tried to determine predictors of such recurrences. Several studies have identified liver regeneration, with its associated growth factors and cytokines, as a potential process that can stimulate tumour growth, thus promoting recurrence1051.

The regenerative ability of the liver after partial liver resection can be affected by the quality of the liver, which can be affected by steatosis52, fibrosis, and cirrhosis53,54. It has been suggested that the degree of liver steatosis is an important indicator of the liver’s regeneration capacity52. Non-alcoholic fatty liver disease (nafld) can range from simple steatosis, to steatohepatitis, and later to fibrosis and cirrhosis. The histologic features that can be present in fatty liver are steatosis, inflammation, hepatocyte ballooning, and fibrosis. Fatty liver disease is increasing in prevalence, affecting 20%–30% of people in North America55. The mechanism by which steatosis affects liver regeneration is not yet clear; however, insulin resistance, defective metabolic gene expression, and abnormal expression of transforming growth factor β1 have been shown to have a role5660. Steatosis and steatohepatitis have also been shown to increase the level of transforming growth factor β, specific metalloproteinases, and oxidative stress, which in turn can facilitate tumour growth and progression6164.

On the other hand, knowing that liver regeneration can have a stimulatory effect on tumour growth and recurrence, and that nafld decreases the liver’s regeneration capacity, there is currently an interest in defining whether fatty liver could have a protective effect with respect to metastatic tumour recurrence—a question that remains unanswered at the present time. Here, we examine the correlations and interplay between the degree of nafld, liver regeneration, and tumour recurrence after hepatectomy for crc-lm.

METHODS

Patients

After obtaining institutional review board approval, a review of our crc-lm database for all R0 liver resections performed for crc-lm at the McGill University Health Centre from January 2007 to January 2012 identified 215 patients. We then excluded patients who did not have, within their electronic medical record, at least 1 preoperative computed tomography (ct) exam and 1 ct exam at 12 or more weeks postoperatively; who had previously undergone portal vein embolization or staged resection; who had undergone procedures, such as liver ablation, that affect liver volume; and for whom histology blocks of the non-tumoural hepatic parenchyma were unavailable for histopathologic analysis. Application of those criteria left 60 evaluable patients, who constituted the study sample (Figure 1).

 


 

FIGURE 1 CONSORT diagram for the study sample. CRC = colorectal cancer; PVE = portal vein embolization; CT = computed tomography.

For the 60 identified patients, the following data were collected from the crc-lm database: patient demographics, surgical procedure details, resection margin status, tumour characteristics, preoperative and postoperative chemotherapy regimens, number of cycles, and date of last cycle. Patient charts and follow-up imaging (ct, positron-emission tomography, and magnetic resonance) were reviewed for any evidence of recurrence. We then recorded the date and site of recurrence. We obtained overall survival duration by chart review and by retrieving death certificates from the Régie de l’assurance maladie du Québec. Any patient who proved to be alive at January 2013 was considered a survivor.

Liver Volumetrics

Preoperative and postoperative (at 12 weeks or more after surgery) ct imaging was retrieved for each patient. The 12-week time point was chosen for the follow-up imaging, because most liver regeneration had occurred by that time65. Volume measurements were performed on axial view, portovenous phase, 2.5 mm thickness, multiphasic ct images. The images were transferred to the Advantage Workstation 4.3 (GE Healthcare, Little Chalfont, U.K.) with dedicated three-dimensional volume calculation software.

Preoperative scans were analyzed for total liver volume before resection (tlvpre-op), future liver remnant (flr), and total tumour burden. To measure the tlvpre-op, the edges of the liver were manually traced on each ct slice, excluding the vena cava, gallbladder, and liver ligaments. The volume was then automatically calculated based on the traced area and slice thickness. The total tumour burden was measured by highlighting each lesion (based on lesion density, the highlight diffuses throughout the slices to cover the whole lesion). The volume was automatically calculated after all lesions had been highlighted.

The edges of the flr were traced according to the Couinaud classification and on the basis of the predicted postoperative outflow anatomy. The selected area was then highlighted, and the volume was automatically calculated. The flr of patients who underwent wedge resection was calculated differently, given that wedge resection is an operator-dependent type of resection. The weight of resected liver was retrieved from the pathology report and was then converted to a cubic volume in centimetres, assuming that liver density is the same as water density. The equation tlv minus volume of resected liver was then applied to yield the flr66.

Imaging was also analyzed for postoperative total liver volume (tlvpost-op). Based on image availability, tlvpost-op was not necessarily measured using portovenous phase ct images because the measurement did not require identification of the venous blood supply. To measure the tlvpost-op, the edges of the liver were manually traced on each ct slice, excluding the vena cava, gallbladder, and liver ligaments. The volume was then automatically calculated based on the traced area and the slice thickness. We excluded postoperative fluid collections from the tlvpost-op when present.

The formula used to calculate the percentage of estimated liver regeneration (%elr)67 was

Degree of NAFLD

Hematoxylin and eosin–stained slides of the non-tumoural hepatic parenchyma were retrieved for each patient and were scored, under the supervision of a liver pathologist, for liver steatosis, lobular inflammation, ballooning and fibrosis per the Kleiner et al.68nafld activity score (Table i). We also studied trichrome-stained slides to score the degree of fibrosis: 0, no fibrosis; 1, peri-sinusoidal, or peri-portal or portal (1a: mild peri-sinusoidal; 1b, moderate peri-sinusoidal; 1c, peri-portal or portal); 2, peri-sinusoidal and peri-portal or portal; 3, bridging fibrosis; 4, cirrhosis. For the present study, we treated 1a, 1b, and 1c as 1 because of the limited variability of the patients.

TABLE I Evaluation tools: non-alcoholic fatty liver disease (NAFLD) activity score and fibrosis staging

 

Statistical Analysis

Statistical analyses were performed using the JMP software application (version 10.0: SAS Institute, Cary, NC, U.S.A.). Normally distributed data are expressed as means and standard deviations; otherwise, medians and ranges are used. Nominal data are expressed as percentages. The Kaplan–Meier method was used to plot curves for time-to-event outcomes (for example, hepatic disease-free survival, overall survival). Cox proportional hazards regression models were used to examine the association between %elr (and other numerical variables) and hepatic disease-free survival and overall survival. The log-rank chi-square test was used with nominal data. The associations between %elr and other variables were examined using regression analyses (linear fit for numerical variables and one-way analysis of variance for nominal variables). Levels of significance were set at 5% for all tests unless otherwise specified. We included age and body mass index (bmi) with cut-offs (>70 years and >30) to all multivariate analysis. On multivariate analysis, only significant variables (p < 0.05), in addition to age and bmi, were tested using proportional hazards.

We tested these variables against hepatic disease-free and overall survival:

  • ■ Liver volumetrics: tlv, flr, tlvpost-op, and %elr

  • ■ Control variables: age, sex, bmi

  • ■ Cancer characteristics: TNM stage; serum carcinoembryonic antigen; lesion size, number, and distribution

  • ■ Resection characteristics: type of resection, disease-free margin

    • nafld score (steatosis, hepatocyte ballooning, lobular inflammation) and fibrosis score

RESULTS

Patient Characteristics

Of the 60 patients eligible for the study (Figure 1), 36 were men (60%) and 24 were women (40%). Table ii presents the demographic characteristics and surgical details for the patients. Median age in the cohort was 68.5 years (range: 40–81 years), and the median bmi was 26.5. Disease was unilateral in 44 patients (73.33%) and bilateral in 16 patients (26.66%). Of the 59 patients for whom synchronicity was known, disease was synchronous in 28 (47.45%) and metachronous in 31 (52.54%). Median TNM staging was T3N1M1. Lesions were larger than 5 cm in 8 patients (13.33%).

TABLE II Baseline characteristics of the study patients

 

In this cohort, 32 patients underwent right hepatectomy (53.33%), 9 underwent left hepatectomy (15%), 10 underwent left lateral hepatectomy (16.66%), and only 3 patients underwent right tri-segmentectomy. The rest either underwent wedge resection, single segmentectomy, or bi-segmentectomy (Table ii).

Table iii summarizes the liver volumetrics. The median estimated liver regeneration was 74.57% (range: −9.95% to as high as 324.32%).

TABLE III Liver volumetrics

 

The median percentage of total steatosis was 12.5% (range: 0%–85%), the median percentage of micro-steatosis was 5% (range: 0%–50%), and the median percentage of macro-steatosis was 7.5% (range: 0%–75%). Table iv summarizes the nafld and fibrosis scores.

TABLE IV Histologic features of non-alcoholic fatty liver disease

 

Complete data on preoperative chemotherapy were available for 59 patients. Of those 59 patients, 46 received preoperative therapy. The type of preoperative chemotherapy was identified for 41 patients. The median number of preoperative chemotherapy cycles was 6. The median interval between the last preoperative chemotherapy cycle and surgery was 7 weeks.

The median length of follow-up in the cohort was 27.5 months. The hepatic recurrence rate was 38.33%. Hepatic disease-free survival at 5 years was 48%, and the median survival duration was 56 months. Overall survival at 5 years was 39%, and the median survival duration was 56 months (Table v). Figure 2 shows the Kaplan–Meier curves for hepatic disease-free and overall survival.

TABLE V Survival results

 

 


 

FIGURE 2 Kaplan–Meier survival curves for patients eligible to test the secondary hypothesis. (A) Hepatic disease-free survival was 78% at 1 year, 58% at 3 years, and 48% at 5 years. Median survival duration was 56 months. (B) Overall survival was 98% at 1 year, 62% at 3 years, and 39% at 5 years. Median survival duration was 56 months.

Predictors of Hepatic Disease-Free Survival

Univariate analysis of the study cohort revealed that a higher degree of hepatocyte ballooning was associated with an increased risk of hepatic recurrence and significantly decreased hepatic disease-free survival (risk ratio: 3.31; p = 0.003; Figure 3). It also showed that lesions of 5 cm or larger (p = 0.043) and synchronous disease (p = 0.025) were associated with an increased risk of hepatic recurrence. The type of resection was also significantly associated with hepatic disease-free survival (p = 0.03), such that disease-free survival was best after right hepatectomy (median survival duration: 56 months) and worst after wedge resection (median survival duration: 7 months). On the other hand, the degree of steatosis had no significant association with risk (p = 0.68), and other histopathologic features, including lobular inflammation and fibrosis, had no significant association with hepatic disease-free survival (Table iv).

 


 

FIGURE 3 Univariate analysis evaluating the severity of histologic features of non-alcoholic fatty liver disease with respect to hepatic disease-free survival in patients eligible to test the secondary hypothesis. Correlations with lobular inflammation severity (p = 0.32) and fibrosis stage (p = 0.74) were nonsignificant. Severity of hepatocyte ballooning was significantly associated with decreased hepatic disease-free survival (p = 0.003). Solid line = median; dotted line = mean.

On multivariate analysis (whose variables included hepatocyte ballooning, lesion diameter, synchronous disease, and type of resection, plus age and bmi), only hepatocyte ballooning (p = 0.0009), maximum lesion diameter (p = 0.014), and synchronous disease (p = 0.006) proved to be significantly correlated with survival, with ballooning having the strongest correlations (Tables iiiv)

The Severity of NAFLD and %ELR

On univariate analysis, a significant correlation was observed between %elr and lobular inflammation. The higher the degree of lobular inflammation, the lower the liver capacity to regenerate (estimate: −54.31; p = 0.003). Results for stage of fibrosis were similar (estimate: −39.9; p < 0.001). Other factors that significantly correlated with liver regeneration included flr (estimate: −0.14; p < 0.0001), number of segments resected (estimate: 40.80; p < 0.0001), major resection (mean: 114.75%; range: 93.65%–135%; p < 0.001), and number of lesions (estimate: 17.27; p = 0.01). Neither hepatocyte ballooning nor steatosis significantly correlated with regeneration capacity of the liver (p = 0.70 and p = 0.35 respectively, Figure 4).

 


 

FIGURE 4 Regression analysis evaluating the severity of histologic features of non-alcoholic fatty liver disease with respect to the percentage estimated liver regeneration (%ELR) in patients eligible to test the secondary hypothesis. (A) The %ELR did not significantly correlate with severity of steatosis (p = 0.35). (B) The %ELR was significantly decreased with severity of lobular inflammation on univariate analysis (p = 0.003), but not on multivariate analysis (p = 0.21). (C) The %ELR did not significantly correlate with severity of hepatocyte ballooning (p = 0.7). (D) The %ELR was significantly decreased with severity of fibrosis on univariate analysis (p = 0.0004), but not on multivariate analysis (p = 0.89).

Multivariate analysis of the significant variables (including degree of lobular inflammation, stage of fibroses, major resection, number of lobes resected, flr, and number of lesions, plus age greater than 70 years and bmi greater than 30), showed that only flr is a statistically significant predictor of liver regeneration (p < 0.01).

DISCUSSION

In the present study, we investigated the relationships of severity of nafld (based on histologic features) with risk of recurrence and with the regeneration capacity of the liver after hepatectomy for patients with crc-lm. The study showed that hepatocyte ballooning is associated with an increased risk of crc-lm recurrence. And yet the degree of steatosis did not predict the risk of recurrence nor the capacity of the liver to regenerate.

We also examined the effect on tumour recurrence of each nafld histologic feature separately and looked into the effect of micro- and macro-steatosis. Hamady et al.69 concluded that liver steatosis is an independent predictor for disease recurrence. On the other hand, Murono et al.70 found that crc-lm occurs less frequently in fatty livers after resection, suggesting that steatosis might provide an unfavourable environment for metastasis in liver. However, in the present study, we found that steatosis does not predict hepatic disease-free survival. That discrepancy could reflect the fact that Hamady et al. and Murono et al. divided patients into two groups (steatosis and no steatosis) and did not consider the severity of steatosis. In contrast, we considered the steatosis score as well as the percentages of total steatosis, micro-steatosis, and macro-steatosis. The other two studies assessed steatosis using different methods: Hamady et al. used histologic assessment, and Murono et al. used radiologic liver density and liver-to-spleen density ratio. In our cohort, the only nafld histologic feature that was associated with decreased hepatic disease free-survival was hepatocyte ballooning.

Hepatic disease-free survival was also inferior in the presence of synchronous disease compared with metachronous disease (69% at 1 year and 25% at 5 years vs. 85% at 1 year and 75% at 5 years), a result that accords with the reports of Yamada el al.71 and Fong et al.72. Hepatic disease-free survival in our cohort was inferior for lesions 5 cm in diameter or larger than for smaller lesions (50% at 1 year and 33% at 5 years vs. 81% at 1 year and 40% at 5 years), a result that also accords with the literature71,72. However, in contrast to the results reported by Yamada el at.71, we found no correlation of preoperative serum carcinoembryonic antigen, diameter of the largest nodule, number of positive lymph nodes, or bilateral disease involvement with disease-free survival.

Our study revealed interesting trends. Each histologic feature of nafld appears to have different effects on %elr. Severity of steatosis (steatosis score and the percentages of total steatosis, of micro-steatosis, and of macro-steatosis), lobular inflammation, and stage of fibrosis tended to be associated with decreased liver regeneration capacity; however, only the latter two features reached the level of significance on univariate analysis. On the other hand, hepatocyte ballooning showed a trend toward association with increased liver regeneration capacity, but that trend did not reach the level of significance.

We also found that major resection, a larger number of resected segments, and a larger number of lesions were associated with increased %elr. Those results are consistent with our findings in a different patient cohort from the same centre73. Higher %elr is seen with trisegmentectomy, and the lowest %elr with wedge resection. The 2 patients who underwent single-segment resection actually had minor liver regeneration; smaller resections provide less of a growth stimulus.

Even though our study was carefully prepared, it has several limitations that should be taken into account. First, the sample size was small because of the exclusions based the availability of ct imaging at appropriate time points. Second, the retrospective nature of the study limited our access to some information, resulting in missing data such as the number of positive lymph nodes associated with the primary disease. Third, the limited variability in the degree of ballooning, such that only 4 of the 60 included patients showed grade 0 ballooning, could have biased the results. Nevertheless, the study raises an important concern about the effect of ballooning on liver disease.

CONCLUSIONS

In our patient population, hepatocyte ballooning might have had a negative effect on hepatic disease-free survival; however, the degree of liver steatosis did not correlate with the hepatic recurrence rate or liver regeneration capacity.

ACKNOWLEDGMENTS

Part of the present work was presented as a poster at the 2014 Clinical Congress of the American College of Surgeons; 26–30 October 2014; San Francisco, CA, U.S.A.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS

*Department of Surgery, Section of Hepatopancreatobiliary, and,
Department of Radiology, McGill University Health Centre, Montreal, QC;,
Department of Radiology and,
§Department of Surgery, King Saud University, Riyadh, Saudi Arabia;,
Department of Pathology, McGill University Health Centre, Montreal, QC..

REFERENCES

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–49.
cross-ref  pubmed  

2. Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981;141:586–9.
cross-ref  pubmed  

3. Goslin R, Steele G Jr, Zamcheck N, Mayer R, MacIntyre J. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 1982;25:749–54.
cross-ref  pubmed  

4. de Brauw LM, van de Velde CJ, Bouwhuis-Hoogerwerf ML, Zwaveling A. Diagnostic evaluation and survival analysis of colorectal cancer patients with liver metastases. J Surg Oncol 1987;34:81–6.
cross-ref  pubmed  

5. Fong Y, Kemeny N, Paty P, Blumgart LH, Cohen AM. Treatment of colorectal cancer: hepatic metastasis. Semin Surg Oncol 1996;12:219–52.
cross-ref  pubmed  

6. von Heesen M, Schuld J, Sperling J, et al. Parenchyma-preserving hepatic resection for colorectal liver metastases. Langenbecks Arch Surg 2012;397:383–95.
cross-ref  

7. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982–99.
cross-ref  pubmed  pmc  

8. Jaeck D, Bachellier P, Guiguet M, et al. Long-term survival following resection of colorectal hepatic metastases. Association Francaise de Chirurgie. Br J Surg 1997;84:977–80.
cross-ref  pubmed  

9. Wanebo HJ, Chu QD, Avradopoulos KA, Vezeridis MP. Current perspectives on repeat hepatic resection for colorectal carcinoma: a review. Surgery 1996;119:361–71.
cross-ref  pubmed  

10. Wright JA, Turley EA, Greenberg AH. Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy. Crit Rev Oncog 1993;4:473–92.
pubmed  

11. Thenappan A, Li Y, Shetty K, Johnson L, Reddy EP, Mishra L. New therapeutics targeting colon cancer stem cells. Curr Colorectal Cancer Rep 2009;5:209.
cross-ref  

12. Yang EY, Moses HL. Transforming growth factor beta 1–induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol 1990;111:731–41.
cross-ref  pubmed  pmc  

13. Shipley GD, Pittelkow MR, Wille JJ Jr, Scott RE, Moses HL. Reversible inhibition of normal human prokeratinocyte proliferation by type beta transforming growth factor–growth inhibitor in serum-free medium. Cancer Res 1986;46:2068–71.
pubmed  

14. Tada T, Ohzeki S, Utsumi K, et al. Transforming growth factorbeta–induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol 1991;146:1077–82.
pubmed  

15. Raghow R, Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Transforming growth factor-beta increases steady state levels of type i procollagen and fibronectin messenger rnas posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest 1987;79:1285–8.
cross-ref  pubmed  pmc  

16. Tsushima H, Ito N, Tamura S, et al. Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 2001;7:1258–62.
pubmed  

17. Matsumoto K, Date K, Ohmichi H, Nakamura T. Hepatocyte growth factor in lung morphogenesis and tumor invasion: role as a mediator in epithelium–mesenchyme and tumor–stroma interactions. Cancer Chemother Pharmacol 1996;38(suppl):S42–7.
cross-ref  

18. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-Met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 2004;101:4477–82.
cross-ref  pubmed  pmc  

19. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor–stromal interactions. Cancer Res 1997;57:3305–13.
pubmed  

20. Di Renzo MF, Olivero M, Giacomini A, et al. Overexpression and amplification of the Met/hgf receptor gene during the progression of colorectal cancer. Clin Cancer Res 1995;1:147–54.
pubmed  

21. Bauer TW, Fan F, Liu W, et al. Insulinlike growth factor-i–mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. Ann Surg 2005;241:748–56.
cross-ref  

22. Ager EI, Neo J, Christophi C. The renin–angiotensin system and malignancy. Carcinogenesis 2008;29:1675–84.
cross-ref  pubmed  

23. Yayama K, Miyagi R, Sugiyama K, Sugaya T, Fukamizu A, Okamoto H. Angiotensin ii regulates liver regeneration via type 1 receptor following partial hepatectomy in mice. Biol Pharm Bull 2008;31:1356–61.
cross-ref  pubmed  

24. Ramalho FS, Alfany-Fernandez I, Casillas-Ramirez A, et al. Are angiotensin ii receptor antagonists useful strategies in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia–reperfusion? J Pharmacol Exp Ther 2009;329:130–40.
cross-ref  pubmed  

25. Deshayes F, Nahmias C. Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab 2005;16:293–9.
cross-ref  pubmed  

26. Tea BS, Der Sarkissian S, Touyz RM, Hamet P, deBlois D. Proapoptotic and growth-inhibitory role of angiotensin ii type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. Hypertension 2000;35:1069–73.
cross-ref  pubmed  

27. Pupilli C, Lasagni L, Romagnani P, et al. Angiotensin ii stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells. J Am Soc Nephrol 1999;10:245–55.
pubmed  

28. Leung PS, Suen PM, Ip SP, Yip CK, Chen G, Lai PB. Expression and localization of at1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. Regul Pept 2003;116:61–9.
cross-ref  pubmed  

29. Fujiyama S, Matsubara H, Nozawa Y, et al. Angiotensin at1 and at2 receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (egf)–mediated egf receptor transactivation. Circ Res 2001;88:22–9. [Retraction in: Circ Res 2013;112:e180]
cross-ref  pubmed  

30. Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-ii type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001;34:745–50.
cross-ref  pubmed  

31. Koh SL, Ager EI, Christophi C. Liver regeneration and tumour stimulation: implications of the renin–angiotensin system. Liver Int 2010;30:1414–26.
cross-ref  pubmed  

32. Yayama K, Sugiyama K, Miyagi R, Okamoto H. Angiotensin-converting enzyme inhibitor enhances liver regeneration following partial hepatectomy: involvement of bradykinin b2 and angiotensin at1 receptors. Biol Pharm Bull 2007;30:591–4.
cross-ref  pubmed  

33. Nakano N, Moriguchi A, Morishita R, et al. Role of angiotensin ii in the regulation of a novel vascular modulator, hepatocyte growth factor (hgf), in experimental hypertensive rats. Hypertension 1997;30:1448–54.
cross-ref  pubmed  

34. Paizis G, Gilbert RE, Cooper ME, et al. Effect of angiotensin ii type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 2001;35:376–85.
cross-ref  pubmed  

35. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–80.
cross-ref  pubmed  

36. Yen L, Benlimame N, Nie ZR, et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol Biol Cell 2002;13:4029–44.
cross-ref  pubmed  pmc  

37. De Jong KP, Stellema R, Karrenbeld A, et al. Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology 1998;28:971–9.
cross-ref  pubmed  

38. Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW. Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res 2002;62:7042–9.
pubmed  

39. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (vegf) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 1998;5:271–8.
cross-ref  pubmed  

40. Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 2005;7:134–53.
cross-ref  pubmed  pmc  

41. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392–401.
cross-ref  pubmed  

42. Spano JP, Lagorce C, Atlan D, et al. Impact of egfr expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16:102–8.
cross-ref  

43. Michalopoulos GK, Khan Z. Liver regeneration, growth factors, and amphiregulin. Gastroenterology 2005;128:503–6.
cross-ref  pubmed  pmc  

44. Harun N, Nikfarjam M, Muralidharan V, Christophi C. Liver regeneration stimulates tumor metastases. J Surg Res 2007;138:284–90.
cross-ref  pubmed  

45. Macaulay VM. Insulin-like growth factors and cancer. Br J Cancer 1992;65:311–20.
cross-ref  pubmed  pmc  

46. Singh P, Dai B, Yallampalli U, Lu X, Schroy PC. Proliferation and differentiation of a human colon cancer cell line (CaCo2) is associated with significant changes in the expression and secretion of insulin-like growth factor (igf) igf-ii and igf binding protein-4: role of igf-ii. Endocrinology 1996;137:1764–74.
cross-ref  pubmed  

47. Yee D, Favoni RE, Lippman ME, Powell DR. Identification of insulin-like growth factor binding proteins in breast cancer cells. Breast Cancer Res Treat 1991;18:3–10.
cross-ref  pubmed  

48. Guerra FK, Eijan AM, Puricelli L, et al. Varying patterns of expression of insulin-like growth factors i and ii and their receptors in murine mammary adenocarcinomas of different metastasizing ability. Int J Cancer 1996;65:812–20.
cross-ref  pubmed  

49. Finlay IG, Meek D, Brunton F, McArdle CS. Growth rate of hepatic metastases in colorectal carcinoma. Br J Surg 1988;75:641–4.
cross-ref  pubmed  

50. van der Bij GJ, Oosterling SJ, Meijer S, Beelen RH, van Egmond M. Therapeutic potential of Kupffer cells in prevention of liver metastases outgrowth. Immunobiology 2005;210:259–65.
cross-ref  pubmed  

51. Takeishi T, Hirano K, Kobayashi T, Hasegawa G, Hatakeyama K, Naito M. The role of Kupffer cells in liver regeneration. Arch Histol Cytol 1999;62:413–22.
cross-ref  

52. Rudnick DA, Davidson NO. Functional relationships between lipid metabolism and liver regeneration. Int J Hepatol 2012;2012:549241.
cross-ref  pubmed  pmc  

53. Maros T, Seres-Sturm L, Lakatos O, Seres-Sturm M, Mody E, Blazsek V. Data regarding the restorative effects of the partial removal of the liver in advanced stages of toxic cirrhosis. Morphol Embryol (Bucur) 1975;21:213–17.

54. Haney A, Peacock EE Jr, Madden JW. Liver regeneration and hepatic collagen deposition in rats with dimethylnitrosamine-induced cirrhosis. Ann Surg 1972;175:863–9.
cross-ref  pubmed  pmc  

55. Schreuder TC, Verwer BJ, van Nieuwkerk CM, Mulder CJ. Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol 2008;14:2474–86.
cross-ref  pubmed  pmc  

56. Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979;67:811–16.
cross-ref  pubmed  

57. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106–10.
cross-ref  pubmed  

58. Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Prog Liver Dis 1986;8:283–98.
pubmed  

59. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–31.
cross-ref  pubmed  

60. Tanoue S, Uto H, Kumamoto R, et al. Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat. Biochem Biophys Res Commun 2011;407:163–8.
cross-ref  pubmed  

61. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates tgf-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000;14:163–76.
pubmed  pmc  

62. Imai K, Hiramatsu A, Fukushima D, Pierschbacher MD, Okada Y. Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J 1997;322:809–14.
cross-ref  pubmed  pmc  

63. Kharbanda KK, Rogers DD 2nd, Wyatt TA, Sorrell MF, Tuma DJ. Transforming growth factor-beta induces contraction of activated hepatic stellate cells. J Hepatol 2004;41:60–6.
cross-ref  pubmed  

64. Vendemiale G, Grattagliano I, Caraceni P, et al. Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status. Hepatology 2001;33:808–15.
cross-ref  pubmed  

65. Humar A, Kosari K, Sielaff TD, et al. Liver regeneration after adult living donor and deceased donor split-liver transplants. Liver Transpl 2004;10:374–8.
cross-ref  pubmed  

66. Aoki T, Imamura H, Matsuyama Y, et al. Convergence process of volumetric liver regeneration after living-donor hepatectomy. J Gastrointest Surg 2011;15:1594–601.
cross-ref  pubmed  

67. Kele PG, de Boer M, van der Jagt EJ, Lisman T, Porte RJ. Early hepatic regeneration index and completeness of regeneration at 6 months after partial hepatectomy. Br J Surg 2012;99:1113–19.
cross-ref  pubmed  

68. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–21.
cross-ref  pubmed  

69. Hamady ZZ, Rees M, Welsh FK, et al. Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases. Br J Surg 2013;100:820–6.
cross-ref  pubmed  

70. Murono K, Kitayama J, Tsuno NH, et al. Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Int J Colorectal Dis 2013;28:1065–72.
cross-ref  pubmed  

71. Yamada H, Kondo S, Okushiba S, Morikawa T, Katoh H. Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases. World J Surg 2001;25:1129–33.
cross-ref  pubmed  

72. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18.
cross-ref  pubmed  pmc  

73. Simoneau E, Alanazi R, Alshenaifi J, et al. Neoadjuvant chemotherapy does not impair liver regeneration following hepatectomy or portal vein embolization for colorectal cancer liver metastases. J Surg Oncol 2016;113:449–55.
cross-ref  pubmed  


aThese authors share first co-authorship of the present work. ( Return to Text )

Correspondence to: Peter Metrakos, McGill University Health Centre, Royal Victoria Hospital–Glen Site, 1001 Decarie Boulevard, Room E02.6218, Montreal, Quebec H4A 3J1. E-mail: peter.metrakos@mcgill.ca

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Current Oncology, VOLUME 24, NUMBER 3, June 2017








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