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Hyperglycemia promotes the perineural invasion in pancreatic cancer
Medical Hypotheses (2008) 71, 386–389
www.elsevier.com/locate/mehy
Hyperglycemia promotes the perineural invasion in pancreatic cancer Junhui Li, Qingyong Ma
*
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, China Received 21 April 2008; accepted 28 April 2008
Summary The role of hyperglycemia in perineural invasion in pancreatic cancer is not clear. Pancreatic cancer is characterized by extremely high frequency of perineural invasion (can be as high as 90%, even 100%), which has been associated with poorer survival. In previous epidemiologic, the prevalence of diabetes mellitus in pancreatic cancer is 34–40% and more than half of them are new-onset, which means the course of disease of diabetes mellitus is less than 24 months before cancer diagnosis. The association between diabetes mellitus and pancreatic cancer has long been recognized as that long-standing diabetes mellitus is thought to be an etiologic factor for pancreatic cancer and newonset diabetes mellitus may be a manifestation of the cancer. Long-standing diabetes mellitus can cause peripheral neuropathy. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Diabetes mellitus can also induce the high expression of cytokines such as nerve growth factor to repair the damaged nerves. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hyperglycemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer. Controlling hyperglycemia might reduce the perineural invasion in pancreatic cancer. c 2008 Elsevier Ltd. All rights reserved.
Introduction In the United States, pancreatic cancer (PanCa) ranks as the 9th or 10th most commonly diagnosed * Corresponding author. Tel.: +86 29 8532 3899; fax: +86 29 8532 3473. E-mail addresses: [email protected] (J. Li), qyma56 @mail.xjtu.edu.cn (Q. Ma).
cancer, but is still the fifth leading cause of cancer death in both men and women, accounting for more than 27,000 deaths annually. Its five-year survival rate is still below 5% [1–3]. The dismal prognosis has been linked to local recurrence, lymph node metastasis, liver metastasis, peritoneal dissemination, and perineural invasion (PNI) [4–8]. PanCa is characterized by extremely high fre-
0306-9877/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.05.001
Hyperglycemia promotes the perineural invasion in pancreatic cancer quency of PNI (can be as high as 90%, even 100%) [5], which is an early event. PNI is a common, but not a specific, feature of PanCa. Tumor cells in the perineural space grow in a continuous fashion and may be responsible for some cases of lymphatic spread [9]. The source of pancreatic cancer recurrence, even after apparently curative surgery, is tumor cells hiding in the celiac and superior mesenteric ganglia [10].
The innervation of the pancreas The pancreas is richly supplied with nerves. Sympathetic, parasympathetic, and sensory nerves permeate the pancreas to participate in its normal activities. Deriving from different locations, nerve fibers of different types intermingle as they enter or leave the pancreas, frequently closely adherent to pancreatic arteries [11]. The innervation of the uncinate process of the pancreas originated from the superior mesenteric plexus (SMPlx) along the inferior pancreaticoduodenal artery (IPDA), but did not form a wide offshoot of nerve bundles as reported. Concerning the innervation of the body and tail, it was found that the nerve fibers entered the pancreas immediately after leaving the celiac plexus, and were distributed around the pancreatic duct in a twig-like manner [12].
The mechanism of PNI in PanCa The mechanism of PNI in PanCa is not clear. It can be partly explained by the anatomical proximity of the pancreatic and celiac artery neural plexus. The perineurium is believed to be deficient at three sites: near the nerve ending, at the site invaded by the blood vessels present in nerves, and at the site invaded by reticular fiber [13,14]. Another possible explanation of PNI in PanCa is neurotropism. Because advanced PanCa with PNI expressed numerous types of neuroendocrine markers including S-100, synaprophysin, substance-P, enkephalin, and neural cell adhesion molecules (NCAM) [15]. Other specific factors such as nerve growth factor enhanced the cancer–nerve interaction, providing biological and physical parameters that would explain their frequent and intimate relationship [16–18].
The association between diabetes mellitus and PanCa Diabetes mellitus (DM) was present in 34–40% of patients with pancreatic cancer and frequently is
387
new-onset [19,20]. The mechanism of impaired glucose metabolism that develops in most patients with PanCa is obscure and the association between PanCa and DM is controversial [21]. While longstanding DM is thought to be an etiologic factor for PanCa, new-onset DM may be a manifestation of the cancer [22]. New-onset diabetes was associated with a significantly increased rate of pancreatic cancer diagnosis, particularly in the first 2 years after diabetes diagnosis [23]. The primary endocrine alteration in the tumor area suggests that cancer cells produce diabetogenic substances [24]. Hyperglycemia generates different effects to cancer cells and nerve.
Hyperglycemia–nerve interaction Neurons have a constantly high glucose demand and its glucose uptake depends on the extracellular concentration of glucose. Though, cellular damage can ensue after persistent episodes of hyperglycemia – a phenomenon referred to as glucose neurotoxicity. DM renders several types of nerve damage, including diffuse damage (polyneuropathy) and focal damage (mononeuropathy). Both contribute to sensory and motor deficits and both are associated with significant disability in patients. The molecular mechanisms of neurotoxicity include polyol pathway, glucose-driven oxidative stress and protein glycation [25,26]. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Neuropathy frequently results in clinically significant morbidities, such as pain, loss of sensation, foot ulcers, gangrene and amputations [27,28].
Hyperglycemia–cancer interaction In diabetic individuals, hyperglycemia in susceptible cells results in the overproduction of superoxide by the mitochondrial electron-transport chain, and this process is the key to initiating all damaging pathways related to diabetes [29]. In the pancreatic duct adenocarcinoma cell line Capan-1, hyperglycemia specifically activates the polyol pathway through increased expression and activity of aldose reductase [30]. These findings suggest that hyperglycemia may be directly contributing to oxidative stress in pancreatic and then active the protein kinase C and NF-RB pathway, through which hyper-
388 glycemia could directly contribute to pancreatic cancer [31]. The elevated serum glucose level is advantageous for the increased DNA synthesis of the tumor cells. Hyperglycemia leads to a nonenzymatic glycation of protein structures, and the glycated products enhance the deliberation of free radicals, cytokines and growth factors [32]. There is an increased risk of renal cell carcinoma in human diabetes mellitus. Nephrocarcinogenesis in diabetic rats results from sustained hyperglycemia, resulting in an adaptive metabolic response, altered growth factor signalling and subsequent neoplastic transformation of the tubular epithelial cells [33]. Glucose concentrations may also be an important factor in breast cancer cell because the prevalence of breast cancer is high in diabetic patients [34–37]. Streptozotocin-diabetes promotes the growth of the N-nitrosobis-(2-hydroxypropyl)amine (BHP)-induced pancreatic adenocarcinoma cell line, H2T, implanted in the cheek pouch of the Syrian hamster [38,39]. MCF-7 human breast cancer cell proliferation was increased when glucose concentration in the culture medium was increased. The finding that leptin and high glucose induced up-regulation of cdk2 and cyclin D1 indicates that MCF-7 cell proliferation was activated through the alteration of cell checkpoints that accelerate cell cycle progression [40]. Three factors exist in the microenvironment of pancreatic cancer tissue, which are cancer cells, hyperglycemia and nerves. We can conclude that hyperglycemia generates different effects to cancer cells and nerve. These effects may help us to study the PNI in PanCa by which hyperglycemia can promote the PNI in PanCa.
The hypothesis Pancreatic cancer is characterized by extremely high frequency of perineural invasion, which has been associated with poorer survival. Diabetes has a high prevalence in pancreatic cancer and frequently is new-onset. In cancer patients with hyperglycemia or type 2 diabetes, the rate of tumor recurrence, metastatic spread and fatal outcome is higher as compared with the tumor patients without metabolic disease [20]. Three factors exist in the microenvironment of pancreatic cancer tissue, which are cancer cells, hyperglycemia and nerves. The interactions among them have not been elucidated, as we know that hyperglycemia generates different effects to cancer cells and nerve. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hypergly-
Li and Ma cemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer.
Future implication PanCa is characterized by extremely high frequency of PNI and DM, which has been associated with poorer survival. The mechanism as to how hyperglycemia participates in PanCa with PNI remains to be determined. It is meaningful to discuss the relationship among hyperglycemia, PanCa and nerves, which would probably provide a new mechanism that the hyperglycemia can promote the PNI in PanCa. Blood glucose is an important factor for recovery in cancer patients and controlling hyperglycemia is an adjunct to cancer therapy [41]. On the one hand, controlling hyperglycemia can reduce the proliferation and migration of cancer cell, which also reduce the production of some cytokines such as nerve growth factor. This can attenuate the cancer–nerve interaction. On the other hand, controlling hyperglycemia can attenuate the damage of hyperglycemia to nerves, which can remain the integrity of structure and function. This can improve the quality of life and survival of patients. It means that controlling hyperglycemia can reduce the PNI in PanCa by these two mechanisms. So controlling hyperglycemia also can be an adjunct to cancer therapy.
Acknowledgements This hypothesis is the continuation of previous publications related to PNI in PanCa. This work was supported by grant from Natural Science Foundation of Shaanxi Scientific and Technical Bureau (Grant serial No. 2006C209).
References [1] Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993;43(1):7–26. [2] Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;76:1671–7.
Hyperglycemia promotes the perineural invasion in pancreatic cancer [3] Cooperman AM. Pancreatic cancer: the bigger picture. Surg Clin North Am 2001;81:557–74. [4] Hirai I, Kimura W, Ozawa K, et al. Perineural invasion in pancreatic cancer. Pancreas 2002;24:15–25. [5] Nakao A, Harada A, Nonami T, Kaneko T, Takagi H. Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer. Pancreas 1996;12: 357–61. [6] Ohyama R. Clinicopathological studies on carcinoma of the pancreas with special reference to pathological factors affecting the prognosis and lymph node involvement. Nippon Geka Gakkai Zasshi 1984;85:820–34. [7] Nagakawa T, Konishi I, Ueno K, Ohta T, Kayahara M. A clinical study on lymphatic flow in carcinoma of the pancreatic head area-peripancreatic regional lymph node grouping. Hepatogastroenterology 1993;40:457–62. [8] Nakai T, Koh K, Kawabe T, Son E, Yoshikawa H, Yasutomi M. Importance of microperineural invasion as a prognostic factor in ampullary carcinoma. Br J Surg 1997;84(10): 1399–401. [9] Kayahara M, Nakagawara H, Kitagawa H, Ohta T. The nature of neural invasion by pancreatic cancer. Pancreas 2007;35(3):218–23. [10] Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer. Pancreas 2003;26(4):322–5. [11] Bockman DE. Nerves in the pancreas: what are they for? Am J Surg 2007;194(4):84–6. [12] Yi SQ, Miwa K, Ohta T, et al. Innervation of the pancreas from the perspective of perineural invasion of pancreatic cancer. Pancreas 2003;27(3):225–9. [13] Nagakawa T, Kayahara M, Ueno K, Ohta T, Konishi I, Miyazaki I. Clinicopathological study on neural invasion to the extrapancreatic nerve plexus in pancreatic cancer. Hepatogastroenterology 1992;39(1):51–5. [14] Liu B, Lu KY. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int 2002;1(3):469–76. [15] Kenmotsu M, Gochi A, Ishii H, et al. Relationship between perineural invasion and local recurrence of rectal carcinoma: a preliminary study with immunohistochemical staining with anti-NCAM: preliminary report. Nippon Geka Gakkai Zasshi 1990;91(11):1759–63. [16] Zhu ZW, Friess H, Wang L, et al. Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res 2001;7(1):105–12. [17] Zhu Z, Kleeff J, Kayed H, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog 2002;35(3): 138–47. [18] Hua ZM, Li Z, Lou DL. Relation of nerve growth factor expression with perineural invasion and pain in pancreatic cancer. Nan Fang Yi Ke Da Xue Xue Bao 2006;26(8): 1251–3. [19] Chari ST, Leibson CL, Rabe KG, et al. Pancreatic cancer– associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134:95–101. [20] Krechler T, Novotny ´ J, Zeman M, et al. Pancreatic carcinoma and diabetes mellitus. Cas Lek Cesk 2004;143(2): 97–100. [21] Saruc M, Pour PM. Diabetes and its relationship to pancreatic carcinoma. Pancreas 2003;26(4):381–7.
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[22] Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol Cancer 2003;2:4. [23] Gupta S, Vittinghoff E, Bertenthal D, et al. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol 2006;4(11):1366–72. [24] Katsumichi I, Pour PM. Diabetes mellitus in pancreatic cancer: is it a causal relationship? Am J Surg 2007;194(4):S71–5. [25] Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008;9(1):36–45. [26] Zochodne DW. Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve 2007;36(2):144–66. [27] Malik RA, Tesfaye S, Newrick PG, et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 2005;48:578–85. [28] Boucek P. Advanced diabetic neuropathy: a point of no return?. Rev Diabet Stud 2006;3(3):143–50. [29] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20. [30] Busik JV, Hootman SR, Greenidge CA, Henry DN. Glucose specific regulation of aldose reductase in capan-1 human pancreatic duct cells in vitro. J Clin Invest 1997;100: 1685–92. [31] Giovannucci E, Michaud D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 2007;132(6):2208–25. [32] Suba Z, Ujpa ´l M. Correlations of insulin resistance and neoplasms. Magy Onkol 2006;50(2):127–35. [33] Dombrowski F, Klotz L, Bannasch P, Evert M. Renal carcinogenesis in models of diabetes in rats: metabolic changes are closely related to neoplastic development. Diabetologia 2007;50(12):2580–90. [34] Talamini R, Franceschi S, Favero A, Negri E, Parazzini F, La Vecchia C. Selected medical conditions and risk of breast cancer. Br J Cancer 1997;75(11):1699–703. [35] La Vecchia C, Negri E, Franceschi S, D’Avanzo B, Boyle P. A case-control study of diabetes mellitus and cancer risk. Br J Cancer 1994;70(5):950–3. [36] Weiderpass E, Gridley G, Persson I, Nyre ´n O, Ekbom A, Adami HO. Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer 1997;71(3): 360–3. [37] Goodman MT, Cologne JB, Moriwaki H, Vaeth M, Mabuchi K. Risk factors for primary breast cancer in Japan: 8-year follow-up of atomic bomb survivors. Prev Med 1997;26(1):144–53. [38] Fisher WE, McCullough PJ, Ray MB, Rogers DH, Bell RH. Diabetes enhances growth of pancreatic carcinoma cells. Surgery 1988;104:431–6. [39] Fisher WE, Muscarella P, Boros LG, Schirmer WJ. Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse. Surgery 1998;123(3):315–20. [40] Okumura M, Yamamoto M, Sakuma H, et al. Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 2002;1592(2):107–16. [41] Krone CA, Ely JT. Controlling hyperglycemia as an adjunct to cancer therapy. Integr Cancer Ther 2005;4(1):25–31.
Available online at www.sciencedirect.com
www.elsevier.com/locate/mehy
Hyperglycemia promotes the perineural invasion in pancreatic cancer Junhui Li, Qingyong Ma
*
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, China Received 21 April 2008; accepted 28 April 2008
Summary The role of hyperglycemia in perineural invasion in pancreatic cancer is not clear. Pancreatic cancer is characterized by extremely high frequency of perineural invasion (can be as high as 90%, even 100%), which has been associated with poorer survival. In previous epidemiologic, the prevalence of diabetes mellitus in pancreatic cancer is 34–40% and more than half of them are new-onset, which means the course of disease of diabetes mellitus is less than 24 months before cancer diagnosis. The association between diabetes mellitus and pancreatic cancer has long been recognized as that long-standing diabetes mellitus is thought to be an etiologic factor for pancreatic cancer and newonset diabetes mellitus may be a manifestation of the cancer. Long-standing diabetes mellitus can cause peripheral neuropathy. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Diabetes mellitus can also induce the high expression of cytokines such as nerve growth factor to repair the damaged nerves. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hyperglycemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer. Controlling hyperglycemia might reduce the perineural invasion in pancreatic cancer. c 2008 Elsevier Ltd. All rights reserved.
Introduction In the United States, pancreatic cancer (PanCa) ranks as the 9th or 10th most commonly diagnosed * Corresponding author. Tel.: +86 29 8532 3899; fax: +86 29 8532 3473. E-mail addresses: [email protected] (J. Li), qyma56 @mail.xjtu.edu.cn (Q. Ma).
cancer, but is still the fifth leading cause of cancer death in both men and women, accounting for more than 27,000 deaths annually. Its five-year survival rate is still below 5% [1–3]. The dismal prognosis has been linked to local recurrence, lymph node metastasis, liver metastasis, peritoneal dissemination, and perineural invasion (PNI) [4–8]. PanCa is characterized by extremely high fre-
0306-9877/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.05.001
Hyperglycemia promotes the perineural invasion in pancreatic cancer quency of PNI (can be as high as 90%, even 100%) [5], which is an early event. PNI is a common, but not a specific, feature of PanCa. Tumor cells in the perineural space grow in a continuous fashion and may be responsible for some cases of lymphatic spread [9]. The source of pancreatic cancer recurrence, even after apparently curative surgery, is tumor cells hiding in the celiac and superior mesenteric ganglia [10].
The innervation of the pancreas The pancreas is richly supplied with nerves. Sympathetic, parasympathetic, and sensory nerves permeate the pancreas to participate in its normal activities. Deriving from different locations, nerve fibers of different types intermingle as they enter or leave the pancreas, frequently closely adherent to pancreatic arteries [11]. The innervation of the uncinate process of the pancreas originated from the superior mesenteric plexus (SMPlx) along the inferior pancreaticoduodenal artery (IPDA), but did not form a wide offshoot of nerve bundles as reported. Concerning the innervation of the body and tail, it was found that the nerve fibers entered the pancreas immediately after leaving the celiac plexus, and were distributed around the pancreatic duct in a twig-like manner [12].
The mechanism of PNI in PanCa The mechanism of PNI in PanCa is not clear. It can be partly explained by the anatomical proximity of the pancreatic and celiac artery neural plexus. The perineurium is believed to be deficient at three sites: near the nerve ending, at the site invaded by the blood vessels present in nerves, and at the site invaded by reticular fiber [13,14]. Another possible explanation of PNI in PanCa is neurotropism. Because advanced PanCa with PNI expressed numerous types of neuroendocrine markers including S-100, synaprophysin, substance-P, enkephalin, and neural cell adhesion molecules (NCAM) [15]. Other specific factors such as nerve growth factor enhanced the cancer–nerve interaction, providing biological and physical parameters that would explain their frequent and intimate relationship [16–18].
The association between diabetes mellitus and PanCa Diabetes mellitus (DM) was present in 34–40% of patients with pancreatic cancer and frequently is
387
new-onset [19,20]. The mechanism of impaired glucose metabolism that develops in most patients with PanCa is obscure and the association between PanCa and DM is controversial [21]. While longstanding DM is thought to be an etiologic factor for PanCa, new-onset DM may be a manifestation of the cancer [22]. New-onset diabetes was associated with a significantly increased rate of pancreatic cancer diagnosis, particularly in the first 2 years after diabetes diagnosis [23]. The primary endocrine alteration in the tumor area suggests that cancer cells produce diabetogenic substances [24]. Hyperglycemia generates different effects to cancer cells and nerve.
Hyperglycemia–nerve interaction Neurons have a constantly high glucose demand and its glucose uptake depends on the extracellular concentration of glucose. Though, cellular damage can ensue after persistent episodes of hyperglycemia – a phenomenon referred to as glucose neurotoxicity. DM renders several types of nerve damage, including diffuse damage (polyneuropathy) and focal damage (mononeuropathy). Both contribute to sensory and motor deficits and both are associated with significant disability in patients. The molecular mechanisms of neurotoxicity include polyol pathway, glucose-driven oxidative stress and protein glycation [25,26]. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Neuropathy frequently results in clinically significant morbidities, such as pain, loss of sensation, foot ulcers, gangrene and amputations [27,28].
Hyperglycemia–cancer interaction In diabetic individuals, hyperglycemia in susceptible cells results in the overproduction of superoxide by the mitochondrial electron-transport chain, and this process is the key to initiating all damaging pathways related to diabetes [29]. In the pancreatic duct adenocarcinoma cell line Capan-1, hyperglycemia specifically activates the polyol pathway through increased expression and activity of aldose reductase [30]. These findings suggest that hyperglycemia may be directly contributing to oxidative stress in pancreatic and then active the protein kinase C and NF-RB pathway, through which hyper-
388 glycemia could directly contribute to pancreatic cancer [31]. The elevated serum glucose level is advantageous for the increased DNA synthesis of the tumor cells. Hyperglycemia leads to a nonenzymatic glycation of protein structures, and the glycated products enhance the deliberation of free radicals, cytokines and growth factors [32]. There is an increased risk of renal cell carcinoma in human diabetes mellitus. Nephrocarcinogenesis in diabetic rats results from sustained hyperglycemia, resulting in an adaptive metabolic response, altered growth factor signalling and subsequent neoplastic transformation of the tubular epithelial cells [33]. Glucose concentrations may also be an important factor in breast cancer cell because the prevalence of breast cancer is high in diabetic patients [34–37]. Streptozotocin-diabetes promotes the growth of the N-nitrosobis-(2-hydroxypropyl)amine (BHP)-induced pancreatic adenocarcinoma cell line, H2T, implanted in the cheek pouch of the Syrian hamster [38,39]. MCF-7 human breast cancer cell proliferation was increased when glucose concentration in the culture medium was increased. The finding that leptin and high glucose induced up-regulation of cdk2 and cyclin D1 indicates that MCF-7 cell proliferation was activated through the alteration of cell checkpoints that accelerate cell cycle progression [40]. Three factors exist in the microenvironment of pancreatic cancer tissue, which are cancer cells, hyperglycemia and nerves. We can conclude that hyperglycemia generates different effects to cancer cells and nerve. These effects may help us to study the PNI in PanCa by which hyperglycemia can promote the PNI in PanCa.
The hypothesis Pancreatic cancer is characterized by extremely high frequency of perineural invasion, which has been associated with poorer survival. Diabetes has a high prevalence in pancreatic cancer and frequently is new-onset. In cancer patients with hyperglycemia or type 2 diabetes, the rate of tumor recurrence, metastatic spread and fatal outcome is higher as compared with the tumor patients without metabolic disease [20]. Three factors exist in the microenvironment of pancreatic cancer tissue, which are cancer cells, hyperglycemia and nerves. The interactions among them have not been elucidated, as we know that hyperglycemia generates different effects to cancer cells and nerve. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hypergly-
Li and Ma cemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer.
Future implication PanCa is characterized by extremely high frequency of PNI and DM, which has been associated with poorer survival. The mechanism as to how hyperglycemia participates in PanCa with PNI remains to be determined. It is meaningful to discuss the relationship among hyperglycemia, PanCa and nerves, which would probably provide a new mechanism that the hyperglycemia can promote the PNI in PanCa. Blood glucose is an important factor for recovery in cancer patients and controlling hyperglycemia is an adjunct to cancer therapy [41]. On the one hand, controlling hyperglycemia can reduce the proliferation and migration of cancer cell, which also reduce the production of some cytokines such as nerve growth factor. This can attenuate the cancer–nerve interaction. On the other hand, controlling hyperglycemia can attenuate the damage of hyperglycemia to nerves, which can remain the integrity of structure and function. This can improve the quality of life and survival of patients. It means that controlling hyperglycemia can reduce the PNI in PanCa by these two mechanisms. So controlling hyperglycemia also can be an adjunct to cancer therapy.
Acknowledgements This hypothesis is the continuation of previous publications related to PNI in PanCa. This work was supported by grant from Natural Science Foundation of Shaanxi Scientific and Technical Bureau (Grant serial No. 2006C209).
References [1] Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993;43(1):7–26. [2] Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;76:1671–7.
Hyperglycemia promotes the perineural invasion in pancreatic cancer [3] Cooperman AM. Pancreatic cancer: the bigger picture. Surg Clin North Am 2001;81:557–74. [4] Hirai I, Kimura W, Ozawa K, et al. Perineural invasion in pancreatic cancer. Pancreas 2002;24:15–25. [5] Nakao A, Harada A, Nonami T, Kaneko T, Takagi H. Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer. Pancreas 1996;12: 357–61. [6] Ohyama R. Clinicopathological studies on carcinoma of the pancreas with special reference to pathological factors affecting the prognosis and lymph node involvement. Nippon Geka Gakkai Zasshi 1984;85:820–34. [7] Nagakawa T, Konishi I, Ueno K, Ohta T, Kayahara M. A clinical study on lymphatic flow in carcinoma of the pancreatic head area-peripancreatic regional lymph node grouping. Hepatogastroenterology 1993;40:457–62. [8] Nakai T, Koh K, Kawabe T, Son E, Yoshikawa H, Yasutomi M. Importance of microperineural invasion as a prognostic factor in ampullary carcinoma. Br J Surg 1997;84(10): 1399–401. [9] Kayahara M, Nakagawara H, Kitagawa H, Ohta T. The nature of neural invasion by pancreatic cancer. Pancreas 2007;35(3):218–23. [10] Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer. Pancreas 2003;26(4):322–5. [11] Bockman DE. Nerves in the pancreas: what are they for? Am J Surg 2007;194(4):84–6. [12] Yi SQ, Miwa K, Ohta T, et al. Innervation of the pancreas from the perspective of perineural invasion of pancreatic cancer. Pancreas 2003;27(3):225–9. [13] Nagakawa T, Kayahara M, Ueno K, Ohta T, Konishi I, Miyazaki I. Clinicopathological study on neural invasion to the extrapancreatic nerve plexus in pancreatic cancer. Hepatogastroenterology 1992;39(1):51–5. [14] Liu B, Lu KY. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int 2002;1(3):469–76. [15] Kenmotsu M, Gochi A, Ishii H, et al. Relationship between perineural invasion and local recurrence of rectal carcinoma: a preliminary study with immunohistochemical staining with anti-NCAM: preliminary report. Nippon Geka Gakkai Zasshi 1990;91(11):1759–63. [16] Zhu ZW, Friess H, Wang L, et al. Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res 2001;7(1):105–12. [17] Zhu Z, Kleeff J, Kayed H, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog 2002;35(3): 138–47. [18] Hua ZM, Li Z, Lou DL. Relation of nerve growth factor expression with perineural invasion and pain in pancreatic cancer. Nan Fang Yi Ke Da Xue Xue Bao 2006;26(8): 1251–3. [19] Chari ST, Leibson CL, Rabe KG, et al. Pancreatic cancer– associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134:95–101. [20] Krechler T, Novotny ´ J, Zeman M, et al. Pancreatic carcinoma and diabetes mellitus. Cas Lek Cesk 2004;143(2): 97–100. [21] Saruc M, Pour PM. Diabetes and its relationship to pancreatic carcinoma. Pancreas 2003;26(4):381–7.
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