- Email: [email protected]
Inflammation, a silent killer in cancer is not so silent!
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Inflammation, a silent killer in cancer is not so silent! Editorial overview Bharat B Aggarwal Current Opinion in Pharmacology 2009, 9:347–350 Available online 9th August 2009 1471-4892/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coph.2009.06.018
Bharat B Aggarwal Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]
Dr Bharat B Aggarwal is a professor of Cancer Medicine, Immunology, Biochemistry, Experimental Therapeutics, and chief of the Cytokine Research Laboratory at the University of Texas M. D. Anderson Cancer Center, Houston. He currently holds the Ransom Horne, Jr, Endowed Professorship in Cancer Research. He earned his PhD in biochemistry from the University of California, Berkeley; received postdoctoral training at the University of California Medical Center, San Francisco; and then worked for almost 10 years with Genentech in South San Francisco before moving to Houston, Texas. Dr Aggarwal was the first to isolate TNF-a and TNF-b and identify their receptors. He has published more than 500 original articles in peer-reviewed journals, currently serving on the editorial boards of more than a dozen journals, edited 12 books, and granted 35 patents. He has delivered more than 300 lectures, both nationally and internationally, and has been listed as one of the ‘World’s Most Highly Cited Scientists’. He has received numerous awards, most recently the Ranbaxy Award, an Outstanding Scientist Award from the American Association of Indian Scientists in Cancer Research, and a McCormick Science Institute Research Award from the American Society of Nutrition. The primary focus of Dr Aggarwal’s research is the role of inflammatory pathways in tumorigenesis and other diseases and their modulation by natural products.
www.sciencedirect.com
To think that today’s irritation, an itch, rash, sore throat, cough, swelling, pain here, pain there, bump, or a lump could someday result in cancer, heart attack, allergy, arthritis, diabetes, obesity, osteoporosis, depression, or Alzheimer, though hard to imagine, can be a reality tomorrow. Extensive research within the last half a century has made it clear that human body is made up of approximately 25,000 genes. It is the choreography between these genes and their interaction with the environment has been found to determine whether we are healthy or sick. In fact the word inflammation, the root cause of most chronic diseases, itself is derived from the Latin word ‘inflamacio’, meaning to ‘set a fire’. Inflammation can be either acute or chronic. While acute inflammation is the initial response of the body to harmful stimuli and is short term, chronic inflammation is long term and is the usual predecessor to most chronic diseases [1]. The clinical and cardinal signs of inflammation include redness, swelling, heat, pain, and loss of function. The first four classical signs were described by the Roman physician Cornelius Celsus (ca. 30 BC–38 AD), while loss of function was added by a German physician Rudolf Virchow in 1870. In naming the pathological conditions, inflammation is usually indicated by adding the suffix ‘-itis’, such as bronchitis, esophagitis, gastritis, colitis, pancreatitis, prostitis, cervicitis, and hepatitis. Some conditions such as asthma and pneumonia, although inflammatory conditions, do not follow this convention. It was Rudolf Virchow who first linked inflammation with cancer, atherosclerosis, diabetes, arthritis, obesity, allergy, and other chronic diseases. What triggers inflammation is none other than everyday life style factors including dietary agents (such as fried foods, meat, and high fat), tobacco, UV radiation, alcohol, environmental pollutants (such as diesel, CO, and heavy metals), stress (psychological, chemical, physical, and mechanical), obesity, and infectious agents (such as bacteria and viruses; Figure 1) [2,3]. Inflammation at the molecular level is determined through the expression of inflammatory transcription factors (such as NF-kB and STAT3), inflammatory enzymes (such as COX2, MMP-9, 5LOX, and PLA2), and inflammatory cytokines (such as TNF, IL-1, IL-6, IL-8), and chemokines. Among all these molecules, perhaps the transcription factor NF-kB is the central mediator of inflammation [4–7]. So far, more than 400 different genes have been identified whose expression is regulated by NF-kB and most of them play a major role in inflammation. Most other inflammatory molecules either lie upstream or downstream to NF-kB (see Figure 2). Perhaps TNF is the most potent activator of NF-kB in most types of cells [8,9]. All the risk factors described above have now been shown to activate NF-kB. How these various life style risk factors activate NF-kB, has been recently reviewed by us [1]. Current Opinion in Pharmacology 2009, 9:347–350
348 Cancer
Figure 1
Activation of inflammatory pathway mediated through NF-kB by life-style-related factors such as tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation and environmental stimuli that account for as much as 95% of all cancers. Suppression of inflammatory pathway by lifestyle-related agents such as vegetables, fruits, legumes, grains, spices and exercise (such as Yoga), is indicated.
Figure 2
Activation of various inflammatory pathways that lead to expression of gene products linked to cellular transformation, survival, proliferation, invasion, angiogenesis and metastasis of cancer. Current Opinion in Pharmacology 2009, 9:347–350
www.sciencedirect.com
Editorial overview Aggarwal 349
Figure 3
A model for the regulation of inflammatory biomarkers. Disease is normally because of dysregulation of numerous inflammatory biomarkers (represented by each bulb). Complete inhibition of a single biomarker (such as COX-2) is more likely to be toxic and unlikely to cure the disease. However, downregulation of several biomarkers is more likely to partially inhibit the dysregulated inflammation, being less toxic and more efficient in treating the disease.
Most growth factors that mediate proliferation of tumor cells also activate NF-kB. For instance EGF, whose receptors are overexpressed in almost one-third of all cancers, has been shown to activate NF-kB and mediate proliferation [10]. Inhibitors of various growth factors, such as EGFR (tarceva, iressa, and cetuximab), HER2 (herceptin), VEGF (avastin), and PDGF (sunitinib and sorafanib), have recently been approved by the FDA for cancer treatment. Cyclooxygenase (COX) 2, an enzyme that mediates the production of prostaglandins, is also regulated by NF-kB; and inhibitor of COX2 (celecoxib/celebrex) has been approved for the prevention of colon cancer. Because cancer is mediated through the dysregulation of multiple genes (as many as 300–500), it is unlikely that the modulation of a single growth factor, receptor, kinase, or signaling pathway is likely to have a significant effect on www.sciencedirect.com
the course of the disease. The failure of monotargeted therapies or ‘smart drugs’ are now forcing physicians to try combination therapies and pharmaceutical industry to design multitargeted therapies that were once called ‘dirty drugs’ [11]. Could it be that most adverse events/toxicities associated with targeted therapies are actually because of complete abrogation by given drug (because of high affinity) of a given cell signaling pathway, which is overactive in tumor cells but has normal function in normal cells. Perhaps drugs derived from natural sources have special benefit over restructured synthetic targeted chemicals, because the former are usually multitargeted, exhibit low affinity for a given target, and are relatively safe (see Figure 3). Curcumin, a component of turmeric, and resveratrol from red grapes are some examples that have been shown to regulate multiple targets (including NF-kB, TNF, COX2, HER2, EGFR, and VEGF), to exhibit Current Opinion in Pharmacology 2009, 9:347–350
350 Cancer
relatively low affinity for most targets, and to be quite safe, and yet it has demonstrated efficacy against a wide variety of proinflammatory diseases including cancer [12].
and safer ways to interrupt the inflammatory response for the prevention and treatment of cancer and other chronic diseases.
This special issue of Current Opinions in Pharmacology is devoted to the role of inflammation in cancer. We review how various mediators of inflammation, especially NFkB, are linked to cancer and survival of patients with different cancers in the first chapter. The genetic aspect of inflammation and its relation to cancer is reviewed by El-Omar in the second chapter. The role of inflammation in bronchitis, which leads to lung cancers, is reviewed in Chapter 3 by Rahman. Cigarette smoke that has been linked to almost 30% of all cancers has been shown to activate NF-kB [13]. How NF-kB regulated chemokines mediate inflammation in lung cancer is described in Chapter 4 by Mulshine. The role of inflammation in head and neck cancer, which is again closely linked to tobacco, is described in Chapter 5 by Van Waes. Barrett’s metaplasia, a major risk factor for esophageal cancer closely linked to inflammation, is described in Chapter 6 by Abdel-Latif. Colitis, a major risk factor for colon cancer, and the role of inflammation in this disease, is described by Arber in Chapter 7. Pancreatitis, alcohol, and cigarette smoke and their role in pancreatic cancer are elucidated by Whitcomb in Chapter 8. How inflammation could potentially lead to prostate cancer is described by Nelson in Chapter 9. Metastasis of certain cancers, such as multiple myeloma, breast cancer, and prostate cancer, to bone and thus resulting in bone loss is a major problem in cancer. How inflammatory pathways mediate cancerinduced bone loss is eloquently described by Abu-Amer in Chapter 10. Finally the role of inflammatory pathways in various neurological diseases such as Alzheimer, is discussed by Lahiri in Chapter 11.
References
First, I would like to thank all the contributors of this special issue on inflammation. Second, I would like to thank Kirsten Krooman, Jeanette Bakker, and Gina Walker for their assistance in bringing this special issue. Last, it is my sincere hope that readers will find this issue highly useful in their everyday research efforts to find new
Current Opinion in Pharmacology 2009, 9:347–350
1.
Aggarwal BB, Vijayalekshmi RV, Sung B: Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009, 15:425-430.
2.
Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB: Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-2116.
3.
Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G: Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006, 72:1605-1621.
4.
Aggarwal BB: Nuclear factor-kappaB: the enemy within. Cancer Cell 2004, 6:203-208.
5.
Garg A, Aggarwal BB: Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 2002, 16:1053-1068.
6.
Shishodia S, Aggarwal BB: Nuclear factor-kappaB: a friend or a foe in cancer? Biochem Pharmacol 2004, 68:1071-1080.
7.
Ahn KS, Aggarwal BB: Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci 2005, 1056:218-233.
8.
Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC: The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy 2002, 1:327-341.
9.
Sethi G, Sung B, Aggarwal BB: TNF: a master switch for inflammation to cancer. Front Biosci 2008, 13:5094-5107.
10. Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB: Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene 2007, 26:7324-7332. 11. Aggarwal BB, Danda D, Gupta S, Gehlot P: Models for prevention and treatment of cancer: problems vs promises. Biochem Pharmacol 2009. [Epub ahead of print]. 12. Aggarwal BB, Sung B: Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009, 30:85-94. 13. Shishodia S, Aggarwal BB: Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9. Cancer Res 2004, 64:5004-5012.
www.sciencedirect.com
Inflammation, a silent killer in cancer is not so silent! Editorial overview Bharat B Aggarwal Current Opinion in Pharmacology 2009, 9:347–350 Available online 9th August 2009 1471-4892/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coph.2009.06.018
Bharat B Aggarwal Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]
Dr Bharat B Aggarwal is a professor of Cancer Medicine, Immunology, Biochemistry, Experimental Therapeutics, and chief of the Cytokine Research Laboratory at the University of Texas M. D. Anderson Cancer Center, Houston. He currently holds the Ransom Horne, Jr, Endowed Professorship in Cancer Research. He earned his PhD in biochemistry from the University of California, Berkeley; received postdoctoral training at the University of California Medical Center, San Francisco; and then worked for almost 10 years with Genentech in South San Francisco before moving to Houston, Texas. Dr Aggarwal was the first to isolate TNF-a and TNF-b and identify their receptors. He has published more than 500 original articles in peer-reviewed journals, currently serving on the editorial boards of more than a dozen journals, edited 12 books, and granted 35 patents. He has delivered more than 300 lectures, both nationally and internationally, and has been listed as one of the ‘World’s Most Highly Cited Scientists’. He has received numerous awards, most recently the Ranbaxy Award, an Outstanding Scientist Award from the American Association of Indian Scientists in Cancer Research, and a McCormick Science Institute Research Award from the American Society of Nutrition. The primary focus of Dr Aggarwal’s research is the role of inflammatory pathways in tumorigenesis and other diseases and their modulation by natural products.
www.sciencedirect.com
To think that today’s irritation, an itch, rash, sore throat, cough, swelling, pain here, pain there, bump, or a lump could someday result in cancer, heart attack, allergy, arthritis, diabetes, obesity, osteoporosis, depression, or Alzheimer, though hard to imagine, can be a reality tomorrow. Extensive research within the last half a century has made it clear that human body is made up of approximately 25,000 genes. It is the choreography between these genes and their interaction with the environment has been found to determine whether we are healthy or sick. In fact the word inflammation, the root cause of most chronic diseases, itself is derived from the Latin word ‘inflamacio’, meaning to ‘set a fire’. Inflammation can be either acute or chronic. While acute inflammation is the initial response of the body to harmful stimuli and is short term, chronic inflammation is long term and is the usual predecessor to most chronic diseases [1]. The clinical and cardinal signs of inflammation include redness, swelling, heat, pain, and loss of function. The first four classical signs were described by the Roman physician Cornelius Celsus (ca. 30 BC–38 AD), while loss of function was added by a German physician Rudolf Virchow in 1870. In naming the pathological conditions, inflammation is usually indicated by adding the suffix ‘-itis’, such as bronchitis, esophagitis, gastritis, colitis, pancreatitis, prostitis, cervicitis, and hepatitis. Some conditions such as asthma and pneumonia, although inflammatory conditions, do not follow this convention. It was Rudolf Virchow who first linked inflammation with cancer, atherosclerosis, diabetes, arthritis, obesity, allergy, and other chronic diseases. What triggers inflammation is none other than everyday life style factors including dietary agents (such as fried foods, meat, and high fat), tobacco, UV radiation, alcohol, environmental pollutants (such as diesel, CO, and heavy metals), stress (psychological, chemical, physical, and mechanical), obesity, and infectious agents (such as bacteria and viruses; Figure 1) [2,3]. Inflammation at the molecular level is determined through the expression of inflammatory transcription factors (such as NF-kB and STAT3), inflammatory enzymes (such as COX2, MMP-9, 5LOX, and PLA2), and inflammatory cytokines (such as TNF, IL-1, IL-6, IL-8), and chemokines. Among all these molecules, perhaps the transcription factor NF-kB is the central mediator of inflammation [4–7]. So far, more than 400 different genes have been identified whose expression is regulated by NF-kB and most of them play a major role in inflammation. Most other inflammatory molecules either lie upstream or downstream to NF-kB (see Figure 2). Perhaps TNF is the most potent activator of NF-kB in most types of cells [8,9]. All the risk factors described above have now been shown to activate NF-kB. How these various life style risk factors activate NF-kB, has been recently reviewed by us [1]. Current Opinion in Pharmacology 2009, 9:347–350
348 Cancer
Figure 1
Activation of inflammatory pathway mediated through NF-kB by life-style-related factors such as tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation and environmental stimuli that account for as much as 95% of all cancers. Suppression of inflammatory pathway by lifestyle-related agents such as vegetables, fruits, legumes, grains, spices and exercise (such as Yoga), is indicated.
Figure 2
Activation of various inflammatory pathways that lead to expression of gene products linked to cellular transformation, survival, proliferation, invasion, angiogenesis and metastasis of cancer. Current Opinion in Pharmacology 2009, 9:347–350
www.sciencedirect.com
Editorial overview Aggarwal 349
Figure 3
A model for the regulation of inflammatory biomarkers. Disease is normally because of dysregulation of numerous inflammatory biomarkers (represented by each bulb). Complete inhibition of a single biomarker (such as COX-2) is more likely to be toxic and unlikely to cure the disease. However, downregulation of several biomarkers is more likely to partially inhibit the dysregulated inflammation, being less toxic and more efficient in treating the disease.
Most growth factors that mediate proliferation of tumor cells also activate NF-kB. For instance EGF, whose receptors are overexpressed in almost one-third of all cancers, has been shown to activate NF-kB and mediate proliferation [10]. Inhibitors of various growth factors, such as EGFR (tarceva, iressa, and cetuximab), HER2 (herceptin), VEGF (avastin), and PDGF (sunitinib and sorafanib), have recently been approved by the FDA for cancer treatment. Cyclooxygenase (COX) 2, an enzyme that mediates the production of prostaglandins, is also regulated by NF-kB; and inhibitor of COX2 (celecoxib/celebrex) has been approved for the prevention of colon cancer. Because cancer is mediated through the dysregulation of multiple genes (as many as 300–500), it is unlikely that the modulation of a single growth factor, receptor, kinase, or signaling pathway is likely to have a significant effect on www.sciencedirect.com
the course of the disease. The failure of monotargeted therapies or ‘smart drugs’ are now forcing physicians to try combination therapies and pharmaceutical industry to design multitargeted therapies that were once called ‘dirty drugs’ [11]. Could it be that most adverse events/toxicities associated with targeted therapies are actually because of complete abrogation by given drug (because of high affinity) of a given cell signaling pathway, which is overactive in tumor cells but has normal function in normal cells. Perhaps drugs derived from natural sources have special benefit over restructured synthetic targeted chemicals, because the former are usually multitargeted, exhibit low affinity for a given target, and are relatively safe (see Figure 3). Curcumin, a component of turmeric, and resveratrol from red grapes are some examples that have been shown to regulate multiple targets (including NF-kB, TNF, COX2, HER2, EGFR, and VEGF), to exhibit Current Opinion in Pharmacology 2009, 9:347–350
350 Cancer
relatively low affinity for most targets, and to be quite safe, and yet it has demonstrated efficacy against a wide variety of proinflammatory diseases including cancer [12].
and safer ways to interrupt the inflammatory response for the prevention and treatment of cancer and other chronic diseases.
This special issue of Current Opinions in Pharmacology is devoted to the role of inflammation in cancer. We review how various mediators of inflammation, especially NFkB, are linked to cancer and survival of patients with different cancers in the first chapter. The genetic aspect of inflammation and its relation to cancer is reviewed by El-Omar in the second chapter. The role of inflammation in bronchitis, which leads to lung cancers, is reviewed in Chapter 3 by Rahman. Cigarette smoke that has been linked to almost 30% of all cancers has been shown to activate NF-kB [13]. How NF-kB regulated chemokines mediate inflammation in lung cancer is described in Chapter 4 by Mulshine. The role of inflammation in head and neck cancer, which is again closely linked to tobacco, is described in Chapter 5 by Van Waes. Barrett’s metaplasia, a major risk factor for esophageal cancer closely linked to inflammation, is described in Chapter 6 by Abdel-Latif. Colitis, a major risk factor for colon cancer, and the role of inflammation in this disease, is described by Arber in Chapter 7. Pancreatitis, alcohol, and cigarette smoke and their role in pancreatic cancer are elucidated by Whitcomb in Chapter 8. How inflammation could potentially lead to prostate cancer is described by Nelson in Chapter 9. Metastasis of certain cancers, such as multiple myeloma, breast cancer, and prostate cancer, to bone and thus resulting in bone loss is a major problem in cancer. How inflammatory pathways mediate cancerinduced bone loss is eloquently described by Abu-Amer in Chapter 10. Finally the role of inflammatory pathways in various neurological diseases such as Alzheimer, is discussed by Lahiri in Chapter 11.
References
First, I would like to thank all the contributors of this special issue on inflammation. Second, I would like to thank Kirsten Krooman, Jeanette Bakker, and Gina Walker for their assistance in bringing this special issue. Last, it is my sincere hope that readers will find this issue highly useful in their everyday research efforts to find new
Current Opinion in Pharmacology 2009, 9:347–350
1.
Aggarwal BB, Vijayalekshmi RV, Sung B: Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009, 15:425-430.
2.
Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB: Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-2116.
3.
Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G: Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006, 72:1605-1621.
4.
Aggarwal BB: Nuclear factor-kappaB: the enemy within. Cancer Cell 2004, 6:203-208.
5.
Garg A, Aggarwal BB: Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 2002, 16:1053-1068.
6.
Shishodia S, Aggarwal BB: Nuclear factor-kappaB: a friend or a foe in cancer? Biochem Pharmacol 2004, 68:1071-1080.
7.
Ahn KS, Aggarwal BB: Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci 2005, 1056:218-233.
8.
Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC: The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy 2002, 1:327-341.
9.
Sethi G, Sung B, Aggarwal BB: TNF: a master switch for inflammation to cancer. Front Biosci 2008, 13:5094-5107.
10. Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB: Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene 2007, 26:7324-7332. 11. Aggarwal BB, Danda D, Gupta S, Gehlot P: Models for prevention and treatment of cancer: problems vs promises. Biochem Pharmacol 2009. [Epub ahead of print]. 12. Aggarwal BB, Sung B: Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009, 30:85-94. 13. Shishodia S, Aggarwal BB: Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9. Cancer Res 2004, 64:5004-5012.
www.sciencedirect.com