Cancer Adjuvant Therapy
Background: Cancer Biology in the Context of Adjuvant Therapy
Cancer has a unique place in medicine. In 1971, President Nixon declared war on cancer and signed the National Cancer Act into law (National Cancer Institute 2016). For decades, this adversarial tone took us down a path that aimed to find "better bombs" (chemotherapy and radiation), rather than to try to understand the characteristics of this "enemy."
Through advances in scientific techniques and our ability to collect and analyze data, more is known about this "enemy" today than ever before. These developments have helped uncover much about how natural interventions may affect cancer.
Prevention of Cancer Recurrence
There are important biological differences between preventing cancer from developing in the first place (carcinogenesis) and preventing cancer from growing back (recurrence). The goal of adjuvant therapies is to prevent recurrence by controlling the growth of cancer cells that may be present already in the body.
The tumor microenvironment is the area around a tumor. It consists of cancer cells and non-cancerous cells, along with many other biological substances. The components in the tumor microenvironment influence whether or not the cancer cells will divide (Arvelo 2016). The tumor microenvironment presents many opportunities for adjuvant therapy (Balkwill 2012; Li 2007; Wang 2017). A key goal of adjuvant cancer therapy is to maintain a microenvironment that is not conducive to the growth of cancer and instead promotes its dormancy.
Immune Control of Cancer—Three Phases
It is now accepted that cancer cells arise in the body more often than previously thought, and that immune surveillance plays a key role in keeping them in check. Through a process called immunoediting, interactions between the immune system and cancer cells result in three possible outcomes (Schreiber 2011; Mittal 2014):
- Elimination. Elimination is the successful removal of cancer cells by the immune system.
- Equilibrium. Equilibrium is a dormant state in which some cancer cells have not been completely destroyed, but are not growing.
- Escape. In this scenario, cancer cells have escaped immune control and begin to grow. Eventually, these cancer cells may be discovered as a tumor. Many emerging cancer immunotherapies target immune pathways that prevent escape from occurring (Beatty 2015).
Although elimination of cancer is ideal, attaining equilibrium may be equally effective in terms of patient longevity and quality of life. As the originators of the concept of immunoediting themselves wrote, "Equilibrium … may restrain outgrowth of occult cancers for the lifetime of the host" (Schreiber 2011).
The Role of Inflammation
Acute (short-term) inflammation is necessary for health. Acute inflammation allows us to heal injuries, repair wounds, and overcome infections. The key to the benefits of acute inflammation in these scenarios is that it eventually resolves (Serhan 2005). Chronic systemic inflammation causes ongoing tissue damage and is associated with many chronic diseases, including atherosclerosis and cardiovascular disease (Castro 2017; Tuttolomondo 2012; Tsoupras 2018), insulin resistance and type 2 diabetes (Caputo 2017), dementia (Walker 2017), depression (Berk 2013), sarcopenia (age-related muscle loss) (Dalle 2017), osteoporosis (Pietschmann 2016), and chronic kidney disease (Machowska 2016), as well as cancer (Leonardi 2018).
Minimizing systemic inflammation is an important goal of treatments to address chronic degenerative diseases in general, and cancer specifically (Castro 2017; Franceschi 2014). Accomplishing this is particularly challenging in cancer patients and survivors, because conventional cancer treatments often promote inflammation (Scuric 2017; Vyas 2014).
NF-kappaB is a protein complex that influences many aspects of cellular activity by regulating more than 150 genes involved in inflammation, cell survival, and immune function. Chronic activation or dysregulation of NF-kappaB signaling is a critical factor in cancer and other chronic diseases (Taniguchi 2018; Panday 2016). NF-kappaB overactivation is involved in cancer onset, growth, and metastasis, and it contributes to treatment resistance in cancer cells (de Castro Barbosa 2017). NF-kappaB is thus an attractive target to control the progression of cancer (Zeligs 2016; Durand 2017).
A wide range of natural compounds have been shown to reduce the activity of NF-kappaB. One well-studied natural agent is the polyphenol curcumin (Aggarwal 2007). Curcumin is found in the root of turmeric, and provides the familiar orange color of curry spice blends. Interestingly, many other compounds from spices have been found to inhibit NF-kappaB, including capsaicin, quercetin, piperine, black cumin oil, and thyme (Aggarwal 2007; Oliviero 2016; Agbaria 2015; Samykutty 2013; Chopan 2017; Comalada 2005; Majdalawieh 2017). The effects of these compounds may be a factor in the much lower cancer rates seen in some countries where these spices are consumed daily, such as India (Kunnumakkara 2018). A small study examined a combination of curcumin and quercetin in five patients with familial adenomatous polyposis, a hereditary condition characterized by hundreds of precancerous colon polyps. After six months taking 480 mg of curcumin and 20 mg of quercetin three times daily, all five participants had a decrease in the number and size of polyps in their colon. Overall, the average number of polyps decreased by 60.4% and the average size decreased by 50.9% (Cruz-Correa 2006).
Some other examples of natural agents that have been shown to inhibit NF-kappaB include chrysin, aloe, resveratrol, and epigallocatechin gallate (green tea extract; EGCG) (Tőzsér 2016; Ren 2013; Singh 2011).
Epigenetics is the study of how changes happen in gene function, and how those changes are passed on through cell division and to offspring (Deans 2015). In practice, epigenetic regulation dictates whether genes get expressed (turned on) or silenced (turned off). Epigenetic changes over a lifetime due to factors related to diet, lifestyle, and environmental exposures influence cancer risk (Daniel 2015; Bishop, Ferguson 2015). Furthermore, there is mounting evidence that epigenetic dysregulation leading to widespread modification of gene expression in cancer cells plays a critical role in all stages of tumor progression (Timp 2013). Unlike genetic mutations, epigenetic modifications are potentially reversible, making them especially compelling as targets of conventional and natural therapies (Schnekenburger 2012; Hascher 2014). In fact, natural agents such as green tea, resveratrol, curcumin, lycopene, soy isoflavones, and others appear to improve cellular function through epigenetic mechanisms (Gerhauser 2012; Shukla 2014).
Tumor suppressor genes are segments of the genetic code that prevent and interrupt malignant changes in cells. If a tumor suppressor gene becomes damaged through genetic mutation or is inactivated through epigenetic mechanisms, cancer can develop and grow unchecked (Lee 2010; Morris 2015). Perhaps the best-known tumor suppressor gene is p53, which is mutated in more than 50% of human cancers (Parrales 2015). The polyphenols curcumin, resveratrol, and green tea catechins can reactivate p53 through epigenetic mechanisms in some circumstances (Thakur 2016; Gupta 2012; Das 2015; Thakur 2012; Hardy 2011; Boyanapalli 2015). Similarly, natural compounds may help reactivate other tumor suppressor genes that have been silenced through epigenetics (Dammann 2017; Meeran 2010; Pan 2013; Kim 2016).
Cancer Stem Cells
Cancer stem cells (CSCs) are cancer cells that have the properties of stem cells—namely, they can give rise to new cancer cells. CSCs may arise from existing CSCs or from fully differentiated cancerous cells through a process called dedifferentiation (Batlle 2017). They are thought to be responsible for treatment resistance, metastasis, and recurrence (Peitzsch 2017; Kleffel 2013; De Francesco 2018; Phi 2018).
CSCs are notorious for using multiple survival strategies to evade destruction by chemotherapy and radiation, such as pumping drugs out of their interiors, repairing DNA damage, resisting cell death signals, and entering a quiescent or suspended state (Zeuner 2015; Zhang, Feng 2017; Chen W 2016; Hu 2012). Several plant polyphenols have been shown to increase the sensitivity of CSCs to the tumor killing effects of chemotherapy or radiation, including curcumin (Kanwar 2011), apigenin (Erdogan 2017), and resveratrol (Mohammed 2018).
Targeting CSCs directly with natural therapies is an area of great interest in cancer research (Singh 2017). Agents such as lycopene, resveratrol, garlic, genistein, quercetin, and ginger (Mosehly 2015; Shen 2013; Jung 2014), as well as curcumin alone (Zhu JY 2017) and combined with green tea (Chung 2015), have shown promise in interfering with survival and self-renewal processes of CSCs (Singh 2017). Because CSCs also continue an inflammatory state in the tumor microenvironment by increasing activation of NF-kappaB, agents that block NF-kappaB might help disrupt tumor promotion by CSCs (Vazquez-Santillan 2015; Rinkenbaugh 2016).