Vitamin D and Cancer (portions of a book chapter) - Jan 2024

Vitamin D and cancer Jan 2024

Advances in Food and Nutrition Research https://doi.org/10.1016/bs.afnr.2023.12.002
Ranjana P. Bird

The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term “Cancer” represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.

Introduction

Vitamin D is receiving a great deal of attention from health researchers all over the world for its potential critical role in human health. Several recent research reviews have highlighted its role in skeletal and extra skeletal health (see Section 3). An inadequate vitamin D status in the population has been observed worldwide, with a possible link to chronic diseases such as cancer. This chapter is developed in response to specific questions like; What is vitamin D and how does it function in the human body? What evidence exists for a causal relationship between vitamin D and cancer, and how does vitamin D contribute to cancer development? Why this relationship is important and how much vitamin D is required daily to prevent cancer? These questions served as a conceptual framework for this chapter. This chapter’s content is based on “Foods and Nutritional Sciences” rather than vitamin D as a therapeutic agent or adjuvant to traditional cancer treatments. Several areas of importance emerged during the development of this chapter, which are briefly discussed. The role of vitamin D in Cancer is defined as its non-skeletal health effects. The author holds the view that bone health and its endocrine function, including its role in maintaining plasma calcium and phosphorus, is instrumental in maintaining the health of various organs and disease states including cancer (Yuan & Song, 2022). Therefore, this chapter on vitamin D and cancer will include a discussion on the role of bone as appropriate in a context dependent manner. Expert detailed reviews of various topics briefly covered in the present chapter, are referred, to guide the readers.

Technological and methodological advances have improved our ability to detect specific effects of various physiological responses at the cellular and molecular levels. These approaches have increased our understanding of the nutrient network, including how nutrients interact and how human populations’ genetic and evolutionary backgrounds influence nutrient metabolism and associated responses, which have a net effect on human physiology and health.

Human health is defined differently depending on the expert opinions (Lopez-Otin & Kroemer, 2021). In this chapter, health is defined as the absence of pathological changes, which can be achieved if all bodily systems work together to maintain physiological homeostasis. While carcinogenesis is a complex process that involves numerous molecules, molecular pathways, and crosstalk between them (Méndez-López, 2022, Patterson et al., 2018), which is beyond the scope of this chapter.

Cancer is generally defined as a group or mass of cells capable of dividing uncontrollably and surviving by migrating to a different location more conducive to their growth, known as a malignant tumor or cancer. Several discoveries over the last 20 years have shaped our understanding of the process of carcinogenesis and the recognition that cancer is not a single disease. Cancer development is affected by its cellular origin and surrounding environment in the early stages (tumor macroenvironment), and later by its own ability to create a tumor microenvironment, allowing tumor mass, increasing growth autonomy and adulthood. In addition, for decades, biological heterogeneity among tumors has been observed. Furthermore, it is now known that an organ can develop tumors with intra and inter tumor heterogeneity as transformed clones acquire genotypic and phenotypic plasticity, involving interaction between evolving tumor cells and host tissue (Feunteun et al., 2022). Although not all tumors or cancers are the same, certain characteristics of cancers have been described incorporating advances in cancer research (Hanahan and Weinberg, 2000, Hanahan, 2022).

Cancer cells reside in a mass of tumor microenvironment before migrating to another location. Tumor mass, by exhibiting metabolic, morphological, and genetic plasticity, creates a favorable environment for survival. To survive, they acquire both driver and passenger mutations (Aranda et al., 2015, Feunteun et al., 2022). The development of sporadic cancer takes several years and is influenced by changes and involvement of the entire body systems (Tabassum and Polyak, 2015, Tata et al., 2018, Weaver and Gilbert, 2004). Mutations in normal cells (pre-cancerization of a tissue) have been noted (Jonason et al., 1996, Moore et al., 2020, Rane et al., 2023) without carcinogenic changes, requiring an additional stimulus to initiate the carcinogenic process.

Many transformed cells may not be able to complete their journey due to growth constraints imposed by normal surrounding cells, including immune cells. Only a few cells complete this journey. Such behaviors could be based on coopting the normal cell competition mechanisms in healthy tissues, in which fit cells induce apoptosis in less fit cells (see Bowling, Lawlor, & Rodríguez, 2019; Krotenberg Garcia et al., 2021). Indeed, cell competition has been recognized as being relevant to tumor progression in the sense that cancer cells eliminate both surrounding healthy cells and less fit cancer clones within a tumor by inducing apoptosis (Bowling, et al., 2019). During normal development, competitive cell interactions have been noted for quality control. Kroteberg Garcia et al. (2021) demonstrated in a monolayer or organoid model of intestinal cells, that cancer cells use such interactions to actively eliminate wild-type intestinal cells. Apoptosis caused the elimination of wild-type cells, resulting in increased proliferation of intestinal cancer cells. Thus, cell competition drives cancer cell growth.

It is well known that physiological homeostasis declines with age. Nutrition and lifestyle choices have a significant impact on the aging process. With age-related physiological changes, maintaining nutritional adequacy is critical. It is well established in preclinical models that nutrients play an important role in cancer prevention; however, there is limited information available to determine when precancerous changes become more resistant to growth regulation. Previously, we demonstrated that preneoplastic stages, once established, are resistant to growth modulation by tumor-promoting or tumor-inhibitory diets (Bird, Yao, Lasko, & Good, 1996). In the presence of inflammation, preneoplastic lesions induced by a carcinogen are resistant to apoptotic cell death (Manousaki, Mokry, Ross, Goltzman, & Richards, 2016).

Cancer development, regardless of tissue or organ type, necessitates a failure of physiological homeostasis at a multi-system level. Vitamin D status either promotes or inhibits tumor growth by maintaining or disrupting physiological homeostasis. Examples include the potential involvement of vitamin D in various chronic diseases and the effect of chronic diseases on vitamin D status and carcinogenesis (Bellastella, Scappaticcio, Esposito, Giugliano, & Maiorino, 2018; Fowler & Jones, 2022; Guerra, Schuhmacher, et al., 2007).

Each organ is composed of different cell types that are compartmentalized. For example, the colon is divided into proximal, transverse, and distal compartments, each with its own physiological role, embryonic origin, and sensitivity to tumor development. Each colonic crypt is made up of different types of cells that line the crypt wall and include progenitor, proliferative, and differentiation zones. In the differentiation zone, proliferating cells moving upward from the bottom of the crypt along the crypt wall become fully differentiated and functional when they reach the top of the crypt.

The size of the proliferative zone changes significantly depending on the proliferative stimulus, such as in certain types of inflammation, where differentiated cells eventually slough off, making room for incoming differentiating cells. Normally, stem cells are more susceptible to oncogenic transformation; however, several lines of evidence have changed the field of carcinogenesis and cellular origin of cancer. On the basis of a number of evidence, it is now proposed that tumors could start both in the proliferative zones and the differentiation zones. According to research by Burclaff and Miller (2018), post-mitotic cells in the intestinal epithelium, skin, pancreas, and stomach may dedifferentiate upon injury, program to divide, and contribute to tumorigenesis.

The biological and morphological heterogeneity observed in colonic adenomas and carcinomas, as well as their molecular features, have strengthened the proposal that carcinogenesis leads to the development of heterogeneous cancers (Aranda et al., 2015), which can occur in proliferative as well as differentiated cells and is dependent on the tissue micro-environment (Méndez-López, 2022, Testa et al., 2018). For instance, adenomas, which are precancerous lesions of the colon, can vary in terms of their morphology, propensity to progress to cancer, and mutational spectra. Along with numerous phenotypic and epigenetic alterations, colon cancer can have 2–8 driver mutations (Burclaff and Mills, 2018, Testa et al., 2018a). Most importantly, colon cancer develops not only from proliferating cells (bottom up), but also from differentiated cells present in the upper part of the crypts (Shih et al., 2001).

The differentiated cells in the colon and other organs express more vitamin D teceptor (VDR) than their less differentiated counterparts. VDR expression is reduced in some malignant tissues while increased in others. Progenitor cells in breast tissue give rise to both VDR positive and VDR negative cells. Both can cause breast cancer (Welsh, 2018). Pre-cancerous and cancerous changes in various organs and tissues are thus multiple diseases. Pre-cancerous stages are expected to be more amenable to growth regulation than their advanced stages.

In conclusion, the field of “Cancer Biology” has provided evidence that the term “Cancer” represents a group of diseases based on their cellular origin, types of mutations, their macro and microenvironment, and is influenced by the host’s genome and lifestyle factors. As a result, the biology and stages of cancer development determine the role of various vitamin D cancer-modulating effects or other cancer-preventive effects (Fig. 1). This figure shows how a tissue with different cell types could develop into different transformed clones and into tumors with increasing growth intensity.

A review of various evidence and mechanism(s) involved in vitamin D and cancer, is provided in the following sections.

Section snippets

Food sources of vitamin D and its metabolism
Vitamin D is a fat-soluble seco-steroid that is classified as a hormone due to its endogenous synthesis in the human body and its paracrine and autocrine mechanisms of action, which involve a nuclear steroid hormone receptor.

Vitamin D is typically used as an umbrella term to refer to various forms of vitamin D. However, five different vitamers have been identified, with D2 and D3 being the most common forms to which the human population is exposed. Vitamin D2, ergocalciferol, is derived from . . .

Key outcome from epidemiological studies

Apperly (1941) was the first to report a link between solar radiation and cancer mortality in North America. In an ecological study, Garland and Garland (1980) were the first to propose a possible role of D in reducing colon cancer, observing that in US population exposed to higher sunlight living in Southern US had lower colon cancer rate than their counterparts living in Northern US. This proposal created excitement among researchers interested in understanding the role of vitamin D nutrition .. .

Factors affecting anti-carcinogenic effect of vitamin D
Vitamin D status and activities are affected by several factors (Fig. 2). Plasma homeostasis of Ca++ and phosphate (Pi) is critical for human health. Several evidence points to the fact that D and calcium could exert synergistic as well as an independent role in carcinogenesis. The general observation is that D and calcium exert an inhibitory effect on cancer or a null effect (Baron et al., 2015, Brunner et al., 2011, Lappe and Heaney, 2012, Wactawski-Wende et al., 2006). Calcium exerts its . . .

Overview, conclusion and future perspectives
A vast literature exists pertaining to the health effects of vitamin D and cellular and molecular basis of vitamin D action, especially its role in carcinogenesis. The strongest link between D and cancer is provided by ecological and observational studies. It is convincing that low vitamin D status is linked to higher incidence of various types of cancer and cancer related mortality. Whether a high dosages of D supplementation will reduce cancer incidence is not demonstrated. Nutritional . . . .

Future perspectives
Vitamin D is advocated to have various wide ranging positive effects on human health. Many of its effects are attributed to its ability to inhibit cell proliferation, enhance differentiation, enhance antioxidant potential, reduce inflammation, enhance immunity, and increase apoptosis to name a few. To establish its anticarcinogenic properties it is crucial to explore the following:
1. The role of vitamin D in retarding the growth of early stages as opposed to late stages of cancer development needs . . . .

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VitaminDWiki – Cancer category contains:


Cancers get less Vitamin D when there is a poor Vitamin D Receptor


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