The Significance of Acute Phase Small-for-Size Graft Injury on Tumor Growth and Invasiveness After Liver Transplantation

Man, Kwan; Lo, Chung Mau; Xiao, Jiang; Ng, Kevin Tak‐Pan; Sun, Bai Shun; Ng, Irene Oi–Lin; Cheng, Qiao; Sun, Chris K.; Fan, Sheung Tat

doi:10.1097/sla.0b013e31816ffab6xxx

Cited by 78 publications

(77 citation statements)

References 29 publications

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“…It has been demonstrated that the cellular and molecular changes following hepatectomy, including surgical stress responses, ischemia reperfusion injury can alter the kinetics of tumor growth and thereby contribute to recurrence [16,[62][63][64] . The factors related to the surgical stress itself represent transient changes, whereas the process of liver regeneration can act as a stronger and more sustained stimulus that promotes the growth of occult tumors and neoplastic development.…”

Section: Regeneration Factors Influencing Tumor Growth and Metastasismentioning

confidence: 99%

Effect of liver regeneration on malignant hepatic tumors

Shi

Line

2014

WJG

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Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth, leading to liver tumor recurrence. Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways, where activation and proliferation of mature hepatocytes, hepatic progenitor cells, non-parenchymal liver cells might favor both liver regeneration and tumor growth. This review highlights recent advances of tumor growth and development in the regenerating liver, possible mechanisms and clinical implications. Key words: Hepatocellular carcinoma; Colorectal cancer; Recurrence; Liver regeneration; Hepatic progenitor cell; Epithelial to mesenchymal transition Core tip: The liver has a unique capacity for regeneration after cellular damage or partial removal of tissue, and modern liver surgery relies on this property. Liver regeneration is a complex process involving a large array of growth factors, cytokines and cells to restore hepatic mass and function. Experimental and clinical data indicate that the regeneration signals facilitate the growth of both primary and secondary liver tumors and can alter their malignant potential. This is an important mechanism underlying recurrence after liver surgery. New therapeutic strategies founded on better insight into the relationship between liver regeneration and tumor biology are needed.Shi JH, Line PD. Effect of liver regeneration on malignant hepatic tumors.

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Section: Regeneration Factors Influencing Tumor Growth and Metastasismentioning

confidence: 99%

Effect of liver regeneration on malignant hepatic tumors

Shi

Line

2014

WJG

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“…Initiation and progression of tumor growth in the liver is a multifactorial molecular process that involves complex signaling pathways (RAS/RAF-MAPK, phosphatidylinositol-3 kinase (PI3K)/AKT, WNT/b-catenin, insulin-like growth factor (IGF), hepatocyte growth factor (HGF)/c-MET and the growth factors activating angiogenesis pathways) [12]. It has been found that cellular and molecular changes in the postoperative period of the patients who have undergone liver resection (response to surgical stress, damage due to ischemia-reperfusion) can initiate tumor growth kinetics and thus cause rapid progression [13]. The molecular factors, which are produced in the liver tissue because of surgical stress, can be a powerful stimulus for tumor growth.…”

Section: Signaling Pathways Of Regeneration and Their Impact On The Gmentioning

confidence: 99%

Metabolic changes from liver regeneration after metastatic colorectal cancer surgery

Burlaka

Zvirych²,

Dorozhinskiy³

et al. 2017

Nowotwory. Journal of Oncology

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Background. The pathological effect of the surgical ischemia-reperfusion technique is a cause for the development of liver damage and occurrence of acute liver failure during the postoperative period in cancer patients after major resection as well as after transplantation. Despite the urgency of the problem, most of the pathological processes that accompany the above-mentioned conditions are still only incompletely studied. Objective. To investigate the mechanisms of the damaging effects of stress reaction after liver resection, to evaluate the functional state of residual liver tissue and to find ways to influence the regeneration and apoptosis of the resected liver, which in the future would make the liver surgery safer. Methods. The results of treatment of 15 patients with colorectal cancer (mCRC) and liver metastases, who had undergone surgery in the period from December 2015 to November 2016 at the National Cancer Institute. Determination of the state of the detoxifying function of hepatocytes and the coupling of biological oxidation and phosphorylation in the mitochondria of hepatocytes were performed by electron paramagnetic resonance at the temperature of liquid nitrogen. Results. It has been found that the levels of the oxidized and low-spin forms of cytochrome P-450 in the catalytic cycle of the detoxification system were 0.33 ± 0.08 relative units and 1.11 ± 0.13 relative units, respectively (the normal levels are 0.59 ± 0.03 relative units and 2.56 ± 0.02 relative units). Also, an increase registered in the levels of formation of complexes of NO-FeS-proteins up to the values of 0.33 ± 0.08 relative units (the normal level is 0.14 ± 0.07). We believe that such changes are the cause of disturbances in the energy function of mitochondria and the formation of cell hypoxia, which correlates with an increase of lactate levels in tissue of the future liver remnant. The liver remnant levels are > 2.00 mM/g·tissue, while the normal is 1.80 ± 0.26 mm/g·tissue. This confirms the functioning of hepatocytes under hypoxic conditions. Conclusions. In the residual liver tissue, we have found a decrease in detoxification system deficiency and the energy supply of hepatocytes. In hepatocytes of the future liver remnant, reprogramming of the metabolism of mitochondria from oxidative phosphorylation in glycolysis is registered, resulting in the formation of cell hypoxia and an increase in levels of lactate and superoxide radicals. To assess the degree of ALF in the postoperative period, we suggest use of the levels of lactate, the activity of cytochrome P-450, the levels of formation of complexes of NO and FeS-proteins in mitochondria ETC and the generation rate of SR as the markers. NOWOTWORY J Oncol 2017; 67, 2: 121-126

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“…reported that significant activation of cell signaling pathways caused by this graft injury leads to cell adhesion, angiogenesis, cell invasion, and migration, which promoted tumor growth and metastasis after LT in an animal study (38). Rapid liver regeneration after small-for-size LDLT could also provide a more favorable environment for tumor growth and metastasis, as Shi et al reported, since HCC tumors developing after hepatectomy display growth rates and malignant transformations related to the size of the partial hepatectomy (39).…”

Section: Hypertension Man Et Almentioning

confidence: 99%

“…The inferior results of LDLT have been attributed to growth factors and cytokines released during acute graft injury, and subsequent graft regeneration resulting from the small-for-size graft in LDLT (36)(37)(38)(39) OS, overall survival; RFS, recurrent-free survival; RR, recurrence rate; A2ALL, Adult-to-Adult Living Donor Liver transplantation Cohort Study; N.S., not significant.…”

Section: Hypothesized Mechanism Of Increased Risk Of Recurrence With mentioning

confidence: 99%

Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma

Ogawa¹,

Takada²

2016

Transl. Gastroenterol. Hepatol.

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With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT.

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The Significance of Acute Phase Small-for-Size Graft Injury on Tumor Growth and Invasiveness After Liver Transplantation

Abstract: Significant activation of cell signaling pathways leading to tumor invasion and migration in small-for-size liver grafts promotes tumor growth and metastasis after liver transplantation.

Cited by 78 publications

References 29 publications

Effect of liver regeneration on malignant hepatic tumors

Effect of liver regeneration on malignant hepatic tumors

Metabolic changes from liver regeneration after metastatic colorectal cancer surgery

Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma

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