Pi and Molecular Mechanisms in Tumorigenesis: Comparison
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Please note this is a comparison between Version 3 by Rita Xu and Version 2 by Rita Xu.

Cancer therapeutics have a low success rate in clinical trials. An interdisciplinary approach is needed to translate basic, clinical, and remote fields of research knowledge into novel cancer treatments. Recent research has identified high dietary phosphate intake as a risk factor associated with cancer incidence. A model of tumor dynamics predicted that reducing phosphate levels sequestered in the tumor microenvironment could substantially reduce tumor size. Coincidently, a low-phosphate diet is already in use to help patients with chronic kidney disease manage high serum phosphate levels.

  • cancer
  • low-phosphate diet
  • phosphate toxicity
  • chronic kidney disease

1. Introduction

More than half a century after the U.S. National Cancer Act of 1971 declared war on cancer, Castuera wrote in the American Journal of Economics and Sociology that the war on cancer failed because its main focus was on increasing technological advancements in cancer research rather than developing more programs to save lives [1]. The decades following 1971 saw a continued rise in cancer deaths until a reversal of cancer mortality during the mid-1990s which was “based more on inexpensive anti-smoking and other prevention programs than on expensive treatment methods” [1]. By 2014, the International Agency for Research on Cancer (IARC) declared that the battle against cancer will not be won with treatments alone and that measures to effectively prevent a global crisis in cancer are needed [2].
However, the majority of international cancer research funding continues to be directed toward cancer treatments, while prevention remains the smallest investment category [3]. Yet, current treatments have significant clinical limitations. For example, a recent review of cancer chemotherapies over the past six decades found that the rate of outcome failures for solid tumors ranged between 85 and 95% [4]. Drug therapies cause more harm than benefits for some patients [5], and cancer drugs licensed by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) from 2003 to 2013 improved overall patient survival by an average of only 3.43 months compared to treatments in 2003 [6].
Prescribing higher doses of chemotherapy to cancer patients often provides few improved outcomes while increasing toxicity and harm to patients’ quality of life [7], and large amounts of funding are invested in cancer treatment studies with questionable pretrial data [8]. Consequently, the latest drugs and technologies to treat cancer globally will not increase survival, and greater advocacy is needed for less expensive and more effective cancer treatments, “especially in low- and middle-income countries” [9]. Due to changes in lifestyle and increases in the ageing population, cancer is estimated to affect 21.7 million people by 2030 at a cost of USD 458 billion [9]. Effects of financial toxicity experienced by more than half of U.S. patients treated for cancer include “house repossession, bankruptcy, loss of independence, and relationship breakdowns” [10]. Additionally, “Cancer therapeutics currently have the lowest clinical trial success rate of all major diseases”, and “cancer will soon be the leading cause of mortality in developed countries” [11].
But the situation is not hopeless. Researchers can target the development of simple, inexpensive, effective, accessible, and equitable treatments and prevention strategies to address the increasing social and economic burden of global cancer [9]. “Lateral thinking, rather than an approach directed to a particular cancer, has produced the most breakthroughs historically” [1], and “discoveries in medicine have often come from the most remote and unexpected fields of science” [12]. An abundance of new approaches to cancer can be provided by a collaboration of scientists conducting cross-disciplinary research [13]. According to the National Academies of Sciences, Engineering, and Medicine, interdisciplinary research methods can “solve problems whose solutions are beyond the scope of a single discipline or field of research practice” [14].

2. Diet and Cancer

In an “Introduction to Dietary Research and Cancer” [15], Gacche wrote “Epidemiological studies have clearly demonstrated the fact that diet and nutrition have profound impact and influence on the progression of cancer and also on risk of developing cancers”. Yet, the author also points out gaps in the clinical application of this information such as the need for more evidence from rigorous clinical research and the low impact of nutritional advice due to “moderate interest of clinical oncologists in diet and nutritional interventions”. Of importance, patients who confront cancer become much more aware of the value of their health and are highly motivated to do “everything in their power to increase their chance of survival” [16]. Cancer patients also have a high interest in dietary strategies, and a review of popular diets found that almost half of surveyed cancer patients were sufficiently motivated to change their dietary habits “with the hope that they will improve survival and prevent recurrence” [17]. Information in the present review should be of interest to a broad audience of cancer patients, oncologists, and nutritionists. Among topics in emerging research on diet and cancer, Gacche described “the diet/metabolite-mediated regulation of cancer signaling pathways/growth factors” as well as metastasis and immunosurveillance in cancer biology. Importantly, metabolomics, the study of chemical metabolites derived from metabolic processes “offers an opportunity to develop a biomarker-based approach to dietary assessment in cancer epidemiology” [18]. A 2023 review of nutritional metabolomics in the association of diet and breast cancer described a wide variety of metabolites from fat, protein, carbohydrate, and other nutrients, but significantly, no mention was made of metabolites related to dietary phosphate [19]. Yet, circulating serum Pi derived from dietary phosphorus absorbed in the intestines “functions as a constituent of cellular metabolites” [20]. Accumulation of interstitial Pi in the tumor microenvironment has been identified as a biomarker of cancer progression (metastasis) [21]. Recently, Fu et al. used animal models to lower Pi concentrations in tumors by administering the phosphate binder lanthanum acetate, and the researchers suggested that this procedure might provide a new anticancer strategy to reduce tumor growth and metastatic progression [22]. Lv et al. used the phosphate binder sevelamer in a rabbit model to lower Pi concentrations in tumor grafts, which improved transarterial chemoembolization that blocks the tumor blood supply while increasing tumor accumulation of the chemotherapeutic agent doxorubicin [23]. Bi et al. [24] lowered Pi-induced metabolic stress by using transarterial sevelamer embolization to “occlude the tumor-feeding vessel” and deplete tumor Pi concentrations, leading to inhibition of liver cancer progression in a rabbit model. Furthermore, animal studies have shown that high dietary phosphate increases lung tumorigenesis through cell signaling in the phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway [25]. A high-phosphate diet fed to mice also increased skin tumorigenesis through the N-ras-extracellular signal-regulating kinase 1/2 (ERK1/2) pathway that regulates cell proliferation [26]. Additionally, obesity is a risk factor for cancers in at least 13 sites in humans, and obesity has been associated with increased dietary phosphate and elevated serum levels of hormones that regulate Pi metabolism: fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) [27]. Obesity is also associated with increased intake of ultra-processed foods that are high in phosphate additives, including phosphoric acid in colas [27]. A 2022 systematic review and meta-analysis found that obesity was associated with an increased risk of mortality in prostate cancer [28], and an earlier analysis of 47,885 men in the Health Professionals Follow-Up study found increased risk of lethal and high-grade prostate cancer associated with dietary phosphorus intake [29]. Another 2022 meta-analysis involving 669,080 participants in case–control studies found that high intake of dietary phosphorus and high serum phosphorus concentrations were associated with an 8% and 7% increase in prostate cancer risk, respectively [30]. Higher levels of serum prostate specific antigen (PSA), a biomarker for prostate cancer, were also associated with an intake of dietary phosphorus above 1151 mg per day in a secondary analysis of data from the U.S. National Health and Nutrition Examination Survey (NHANES), 2003–2010 [31]. In 2023, the present authors published a review proposing that the association of alcohol consumption with increased risk of breast cancer is mediated by hyperphosphatemia caused by alcohol-induced rhabdomyolysis which releases intracellular phosphate from skeletal muscle into the serum [32]. Also in 2023, the authors found that a 2.30 relative risk for breast cancer incidence in a cohort of middle-aged U.S. women was associated with >1800 mg dietary phosphorus compared to 800–1000 mg phosphorous recommended by the U.S. National Kidney Foundation for patients with CKD (RR: 2.30; 95% CI: 0.94–5.61; p = 0.07) [33]. Although the study’s small cohort likely reduced statistical significance, these results are supported by evidence in the present review, and further clinical investigations are warranted to test the hypothesis that limiting cancer patients to 800–1000 mg or less of phosphorus a day will reduce and prevent cancer promotion and progression. Furthermore, another 2023 study of the cohort by the present authors found that a greater magnitude of abnormal bone mineral density changes (mineral deposition in osteosclerosis followed by mineral loss in osteoporosis) was associated with women self-reporting breast cancer incidence compared to women remaining cancer-free [34]. This finding implicates phosphate toxicity as a potential contributing factor to bone metastases in metastatic breast cancer, which should also be investigated with a low-phosphate dietary intervention. In contrast to the above findings, a recent analysis of data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial found that dietary phosphorus was not significantly associated with risk of pancreatic cancer in adults [35]. The study examined associations of pancreatic cancer with daily recommended dietary allowances for calcium, magnesium, and phosphorus (700 mg phosphorus [36]) compared to deficient intake of these nutrients. Importantly, effects of excessive nutrient intake were not investigated, and the researchers added “It is biologically plausible that phosphorus is implicated in pancreatic carcinogenesis”. Furthermore, calcium intake in the study was only associated with reduced cancer risk when fat was also consumed, which may be due to the consumption of full-fat dairy products that are high in calcium but lower in phosphorus per calorie compared to low-fat or nonfat dairy products.

3. Pi and Molecular Mechanisms in Tumorigenesis

Hallmarks of cancer metabolism include increased demand for nutrients to support rapid tumor growth and cell proliferation [37][38]. However, evidence of Pi molecular mechanisms in tumorigenesis suggests an opposite dynamic relationship between supply and demand for growth-promoting nutrients. That is, rather than demanding more nutrients for growth, tumorigenesis is associated with a dysregulated oversupply of growth-promoting dietary phosphorus. Phosphate bonded to deoxyribose forms the backbone of nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), which direct the genetic expression of proteins in cell proliferation [39]. A genetic code transcribed from the cell nucleus is transported via messenger RNA (mRNA) to the cell ribosomes for biosynthesis of cell proteins. Early animal research shows that a high-phosphorus diet induced hyperphosphatemia, increased biosynthesis of mRNA, and stimulated hyperplasia in the parathyroid glands, one of the organs that regulates phosphorus metabolism [40]. Researchers also described how liver tumorigenesis was delayed in precancerous tissue when phosphorus incorporation into cellular nucleic acids was depressed [41]. Phosphorus in RNA also contributes significantly to a higher total biomass of phosphorus in malignant tissue compared to normal tissue [42]. Exposure to high Pi levels increases expression of genes in cancer cells that promote angiogenesis and neovascularization which supply blood to the tumor [43]. Additionally, sodium phosphate cotransporter 2b (NaPi2b) is highly expressed in cancer cells of the ovary, lung, thyroid, and breast compared to normal tissue [44]. By comparison, H+-dependent Pi transport in breast cancer cells is five times higher than Na+-dependent Pi transport when the cells are exposed to high extracellular levels of Pi [45], facilitating sequestration of excessive phosphate into the tumor. A biologically plausible advantage of Pi sequestration in tumorigenesis is that it removes potentially lethal and tissue-damaging amounts of serum Pi circulating throughout the body, which may explain why immune system responses appear to protect tumors in putative “tumor immune evasion” [46]. For example, a model with mice that overexpress the tumor-suppression protein P53 reduced tumorigenesis but increased cachexia, including sarcopenia, organ atrophy, skeletal kyphosis, and premature death. These cachexic effects are similar to effects from phosphate toxicity in a model of mice lacking klotho, a regulator of phosphate metabolism [47]. Consequently, if a tumor is destroyed with conventional treatments like radiation or chemotherapy, rapid release of large amounts of intracellular Pi and other cellular constituents into the serum can cause an oncologic emergency known as tumor lysis syndrome [48]. Moreover, surgical removal of a primary tumor is associated with increased tumor recurrence and metastasis [49], which implies a plausible protective response that persistently sequesters dysregulated Pi into tumors. Tumor progression is also associated with inflammation [50], and inflammation in hemodialysis patients is strongly correlated with serum phosphorus levels [51], suggesting that dysregulated phosphate metabolism and hyperphosphatemia are potential mediating factors in the association of inflammation with tumor progression [52]. Additionally, hyperphosphatemia in hemodialysis patients with end-stage renal disease (ESRD) is associated with increased proliferation and complexity of bacterial flora in the gut microbiota compared to controls without ESRD, but increased proliferation ceased as intestinal phosphorus levels were lowered with phosphate binders [53]. Furthermore, “dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis” [54]. The association of intestinal cancer risk with flora dysbiosis may be mediated by high phosphate levels that stimulate microbial overgrowth, and research should investigate the use of phosphate binders or a low-phosphate diet to reduce intestinal phosphate levels, lower the risk of tumorigenesis, and restore normal balance to the gut microbiota.

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