Cancers As Systemic Functional Diseases

PERSPECTIVES CANCERS AS SYSTEMIC EUNCTIONAL DISEASES, PART 2: CLINICAL IMPLICATIONS Jeffrey Bland, PhD, FACN, FACB

Jeffrey Bland, PhD, FACN, FACB, is cofounder ofthe Institute with them. There are biomarkers that identify these stages of distort- for Functional Medicine, Gig Harbor, Washington. Altern Ther ed physiology and reflect the state of fiinction that is consistent with Health Med. 2010;16(3):54-57). cancer. These stages of disturbed physiology include

Editor's note: The following is the final part of a two-part article. Part 1 • carcinogenic alteration, appeared in our Mar/Apr 2010 issue (Cancers as Systemic Functional • altered cellular proliferation, Diseases, Part 1: Defining the Cancer Domain. Altern Ther Health • genomic instability, lAtA.2010;16(2):52-54). • epigenetic alteration, • angiogenesis, and he emerging view is that many cancers, due to pres- • metastasis. ent therapeutics, may become chronic diseases that need to be managed over many years with diet, life- These areas of altered cellular physiology in turn are driven by style, and environment changes.'-^ Management of specific cellular processes such as the patient that is appropriate for the stage of his or Ther disease is dependent upon the availability of biomarkers or • inflammation, screening tests that have been validated to define the status ofthe • altered intercellular signal transduction, individual. Traditionally, four types of screening tests have been • altered mitochondrial bioenergetics, employed, including early-detection screening such as the Pap test, • altered immune surveillance, mammography, dermatology screen, oral screen, and colonoscopy. • chronic opportunistic infection, and The second type of screening is the use of gene-based cellular • altered posttranslational protein structure. tumor-specific markers such as KRAS, the APC gene, TP53 and BAT26 in stool sample DNA, or cytological examination of cells in Each of these areas, in turn, has a series of metabolic markers sputum samples. The third type of screening test is the use of associated with the degree of distortion or alteration in these pro- serum or urine genetic markers including cyclin E, MCM, PCNA, cesses. It is the systems biology pattern of these markers that defines pl6, BCL-2, and VEGF that monitor cell-cycle progression, DNA the "physiological state fiinction" of the individual and aspects of replication, DNA synthesis, cell-cycle control, antiapoptosis, and both his risk of and status related to specific cancers. In a sense, the angiogenesis. One prime example of this is the use of CA-125 as a approach for screening using this concept is to develop a genomic, tumor marker for women with ovarian cancer. The fourth type of proteomic, and metabolomic profile ofthe patient that reflects his or screening test employs soluble serum or urine metabolites to fol- her physiological state fiinction.* low the course of disease such as the use of catecholamine metabo- At first blush, this objective seems daunting and "fiituristic" lites such as vanillylmandelic acid (VMA) and homovanillic acid and outside the scope of what is practical or even possible under the (HVA) in the urine of patients with neuroblastoma. constraints of current technology. It could be argued that this con- Genetic and molecular biological screening tests traditionally cept is conceptually bounded rather than technologically bounded. have been used in following the course of therapy in a well-described Many ofthe tools that are necessary to address the question ofthe form of cancer. Beyond these traditional approaches to cancer status of metabolic distortion associated with cancer are available assessment, however, is emerging another strategy for the assess- today but are not being employed in this conceptual fi'amework.I n ment ofthe fimctional state ofthe patient's physiology that is relat- order to understand which evaluative tools might be needed to prop- ed to both his individual predisposition to cancer as well as the erly implement this strategy, we need to ask which types of disturbed design of a personalized program for the chronic management of physiological fiinctions have been identified to be associated with the cancer survivor. This type of biomarker screening takes its lead the physiological state function of many cancers. This list would fi-om the pioneering work done on the value of prostate-specific include, for example, assessment of antigen (PSA) screening in males for defining the risk and progres- sion of prostate cancer,'" • insulin and insulin-like growth factor signaling; The states of cancer fi-om initiation through promotion and • detoxification pathways; progression have different stages of disturbed metabolism associated • gastrointestinal immune function and enterometabolic

54 ALTERNATIVE THERAPIES, MAY/JUN 2010, VOL, 16, NO, 3 Cancers as Systemic Functional Diseases, Part 2 activity; • urinary organic acid analysis to evaluate integrity ofinterme- • cellular redox, mitochondrial bioenergetics, and oxidative diary metabolism and potential micronutrient insufficiencies; stress; • serum antibody testing for H pylori, Epstein-Barr virus, hepa- • lipid signaling and status including CD36 activity, fatty acid titis B and C, chlamydia, and HfV; and status, and eicosanoid signaling; • sputum cytological evaluation for micronuclei alteration • steroid hormone status and metabolites; and need for increased intake of protective nutrients and • immune status including autoantibody analysis; phytochemicals. • inflammatory signaling mediators; • genomic stability and epigenetic alteration; These represent an ensemble of tests that demonstrate how one • the status ofintermediary metabolism; and might assemble a portfolio of biomarkers for better understanding • occult bacterial or viral infection in the gastrointestinal tract, of the stages of disturbed physiology associated with cancers. The oral cavity, liver, and sinuses. underlying principle for this assessment panel is that specific dis- turbed physiological state fiinctions are associated with the develop- Specific tests are now available for each of these assessment ment and progression of cancer and that by evaluating the areas and can be employed to define the functional status of the parameters that reflect alterations in genomic, proteomic, and patient that is connected to specific disturbed fiinction associated metabolomic status, a better understanding of the most appropriate with tumor initiation, promotion, and progression. The focus of approach to the patient's long-term management of cancer as a this profile is not to diagnose a specific cancer but rather to better chronic disease can be achieved. This approach might be criticized define the physiological state fiinction of the patient that is associ- for excessive reliance upon laboratory testing and therefore thought ated with cancer. As was described in part 1 of this series, cancer is to be unjustified. Rather than argue for a specific panel that can be a proliferative disorder that is associated with alterations in physi- rationalized on the basis of economics, I propose that the concept of ological fianction that gives rise to its pathophysiological architec- how best to approach the patient's physiology that results in an ture of dedifferentiation, altered cellular cycling, angiogenesis, understanding of his or her "oncogenic potential" should be the invasion, and metastasis.* focus of the debate. The resolution of this question can then be fiir- Specific tests that could be included in such a panel of assess- ther refined to determine the most appropriate panel of screening ment of the physiological state fiinction include and biomarker tests to be included in the management of a specific patient. It is well known that genetics alone account for a very small • fasting and 2-hour postprandial glucose and insulin, along proportion of the determinants for cancer'; therefore, understand- with hemoglobin Ale, and advanced glycosylated endprod- ing the topography of the patient's physiology and his or her unique uct proteins (AGEs) and serum IGF-1 levels for aspects of response to the environment seems to be very important in improv- insulin signaling; ing patient outcome, from both an early detection and long-term • acetaminophen and benzoate challenge tests to evaluate management perspective of cancer as a chronic disease. aspects of phase 1 and phase 2 detoxification; • lactulose/mannitol challenge testing, fecal calprotectin EXAMPLES OF HOW TfflS APPROACH COULD IMPROVE and stool microbiology to evaluate gastrointestinal OUTCOME IN THE CANCER PATIENT immune fiinction; The future of the management of cancer is personalized, pre- • serum lipid peroxides, serum 8-hydroxy-deoxyguanosine ventive, participatory, and prospective in its character, as has been (80HdG) levels, serum isoprostanes for oxidative stress, and described by Snyderman et al.' This characterizes the patient- mitochondrial bioenergetics; centered fundamentals of fiinctional medicine as presented in The • erythrocyte fatty acid analysis, plasma CD36, VCAM Textbook of Functional Medicine.^ This form of cancer medicine will and ICAM-1 analysis for lipid contribution to cellular integrate new genomics science with that of genetic-expression pat- proliferation; terns and how they connect to various phenotypic fijnctional bio- • steroid hormone analysis including estrogen hydroxylated markers that serve as "sensors" for understanding the status of the metabolite; patient and his or her response to personalized intervention/man- • autoantibody analysis including antiTPO, ANA, and antigli- agement." Recently, the American Institute for Cancer Research adin antibodies along with genetic analysis of DR2 and DR8 published the largest review of the link between diet, lifestyle, and polymorphisms for gluten reactivity; cancer." The report estimated that more than 40% of breast cancer • vitamin D status through serum analysis of 25-hydroxy D3 cases could be prevented by making relatively straightforward diet as part of immune evaluation; and lifestyle changes. The key to this approach is matching the diet • analysis ofplasma hsCRP, LpPLA2, and uric acid as part of and lifestyle of the person to his or her specific needs. This approach inflammatory assessment; to the management of both the risk and the progression of cancer is • evaluation of lymphocyte telomere length and serum homo- mirrored in the pioneering work ofJose f Issels, MD, which is described cysteine to evaluate genomic instability and epigenetic meth- in his book Cancer: A Second Opinion.^' His vast experience in manag- ylation defects; ing cancer patients resulted in his conclusion that integrafive cancer

Cancers as Systemic Functional Diseases, Part 2 ALTERNATIVE THERAPIES. MAY/JUN 2010. VOL 16, NO. 3 55 therapy employing a personalized approach to managing diet, life- relationship to celiac disease,^"^ It has become very well known that style, and the patient's environment were critically important in celiac disease is associated with genetic polymorphisms of HLA-DQ2 improving patient outcome. Michio Kushi developed his macrobiot- and DQ8 and presents with intestinal lymphogenesis and increased ic dietary approach to cancer prevention and treatment upon the gastrointestinal cancer risk,^ Mechanisms of oncogenesis and car- same principles of a patient-centered dietary and lifestyle interven- cinogenesis have been proposed for the relationship between intesti- tion program that adjusts the patient's distorted physiology and nal inflammation and celiac disease,^' The gastrointestinal-associated doesn't just focus on treatment of the cancer itself," Long-term fol- mucosal immune system represents more than 50% of an individu- low-up studies of breast, prostate, and colorectal cancer survivors al's immune system, and specific types of chronic inflammatory acti- has demonstrated that those who follow a personalized home-based vation of this system are associated with increased oncogenic risk,^™ controlled diet and exercise intervention program have improved Activation of the inflammatory process within the gastrointestinal fiinctional outcomes," It is recognized that primary care in the early system can be determined by evaluating gastrointestinal mucosal phase of cancer treatment has a marked effect that results in both permeability with the lactulose/mannitol challenge test or the use of reduced mortality risk and improvement of prognostic indicators of fecal calprotectin analysis,^' Calprotectin is a protein produced by disturbed physiological fiinctions associated with cancer,"^ The influ- mucosal-associated immune cells that reflect in situ activation of ence of these interventions on the "oncogenic potential" of the inflammatory processes,™ The elimination diet is the traditional patient can be evaluated by following the specific biomarkers that treatment recommended for the patient who has been discovered to relate to the physiological trajectory of the patient's phenotype, have his or her gastrointestinal immune system activated by a food- related substance such as the gluten family of proteins in cereal SPECIFIC EXAMPLES OF HOW THIS MODEL IS APPLIED TO grains,^' It has been reported recently that certain cultivars of wheat MANAGING CANCER AS A CHRONIC ILLNESS may contain more antigenic proteins than others, and therefore the An example of this approach relates to the recognition that increasing prevalence of gluten sensitivity may be due to altered individuals with insulin resistance/hyperinsulinemia and the plant genetics or posttranslational modification of the gluten pro- resultant type 2 diabetes are at an increased risk for cancer,'" teins that have made them more haptenic,^"' The adage of "food of Insulin is a hormone that stimulates cellular proliferation. It is now one is a poison of another" seems very well supported when evaluat- recognized that both hyperinsulinemia and the therapeutic use of ing the connection among gluten, immune activation, and gastroin- certain analogues of insulin may promote excessive stimulation of testinal cancer. It has been reported that germinating the wheat and IGF-1 receptors and trigger mitogenic cellular responses," In activating specific proteases in the grain may lower the immune- women, IGF-1 and estradiol and its 16-hydroxy metabolites have activating effects of the wheat through the breakdown of specific been found to multiply their effect on proliferative changes in immune-activating protein sequences," It has also been reported breast tissue, resulting in increased oncogenic potential," This sug- that certain strains of enteric Bifidobacterium lactis inhibit the gests that evaluation of the patient's insulin sensitivity is important immune-activating effects induced by wheat gluten through their in evaluating oncogenic potential and the sensitivity to therapy in influence on the gastrointestinal immune system,^^ The conclusion both breast and colon cancer,''™ of this example is that by evaluating the specific immune sensitivity of the patient to a common environmental immune inflammation It is interesting to note that the association of disturbed insulin activator (eg, gluten), a program to reduce the inflammatory onco- signaling and oncogenic potential also relates to the observed con- genic burden on the patient's gastrointestinal tract can be personal- nection between the peroxisome proliferator activated receptor ized to his or her specific needs, (PPAR) gamma agonist medications and their therapeutic influence on colon cancer,^' Epidemiological studies have indicated that hyper- A third and final example of the impact on disease outcome triglyceridemia associated with insuUn resistance is related to colon by managing the patient's disturbed physiology and not just the cancer. The PPARs may play a central role in lipid and glucose cancer itself is that of prostate cancer. In 2005, Ornish et al report- metabolism and the risk for colon carcinogenesis. Extensive work ed on the results of interviews of men involved in the Prostate has demonstrated that the PPAR gamma agonist family of thiazoli- Cancer Lifestyle Trial (PCLT) in which men with biopsy-proven dinedione medications can reduce the risk of colorectal cancer prostate cancer with a Gleason score <7 indicated a positive atti- through their role in modulating aspects of insulin action,^' tude about entering the lifestyle intervention program as opposed It is also interesting that CD36 is a tissue marker for immune to "watchful waiting" as the standard of care,^'^ In 2006, a research inflammatory activation and the oxidation of LDL is a marker for group from the University of California at San Francisco Medical cardiovascular disease as well as a tumor marker. This demonstrates Center reported that the PCLT group had a significant reduction in the important connection between arterial inflammation, immune PSA levels as compared to the watchful waiting control group, system activation, and both atherosclerosis and cancer,^^ This once which had elevated PSA levels," The growth of LNCaP prostate again points to the importance of defining the physiological state cancer cells in culture was inhibited almost eight times more by fiinction as the "soil" in which the disease ultimately develops, serum from the PCLT group of patients vs the controls, and these A second example of the application of this systems biology positive outcomes were directly related to the degree of changes in approach to the management of oncogenic risk relates to gastroin- diet and lifestyle. It was further reported that men who made the testinal cancers associated with inflammatory bowel disease and its most significant changes in their diet and lifestyle had the greatest

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