Articles

Tumor Microenvironment Biology

Cancer is a systemic disease, and it is not a solo production but rather an ensemble performance [1]. Cancer cells act as the leading devil, which is supported by a diverse cast of be- nign cells in the surrounding milieu that actively facilitates the malignant progression in a three-dimensional structure. Even under therapeutic conditions, resistant cancer clones frequently emerge and show complex dynamics with spatial and temporal heterogeneity, implying distinct mechanisms of resistance operative at different sites depending on treatment selection pressure [2,3].

The disease is usually initiated as a result of the stepwise accumulation of genetic and epigenetic changes in the epithelial compartment; however, increasing evidence indicates that the tumor microenvironment (TME) can dictate aberrant tissue function and play a critical role in the subsequent development of more advanced and refractory malignancies [4]. Particularly, inappropriate activation of the stroma, including those provoked by the therapeutics, immunomodulation medi- ated by certain TME cell lineages, and distant metastasis induced by the TME components, can potentiate and ac- celerate tumor progression towards a high rate of disease mortality [5].

Physiologically, the stroma in healthy individuals is a physical barrier against tumorigenesis; however, neoplastic cells elicit various changes to convert the adjacent TME into a pathological entity.

The orchestration of such an event implicates migration of stromal cells, remodeling of matrix, and expansion of vasculature [6]. Regional differences under selective pressures, including acidity and hypoxia in the neoplasia, drastically influence its progression, as do distinct environmental factors select for mutations that engender survival and repopulation of cancer cells, eventually creating tumor heterogeneity and causing treatment difficulty [7].

In this review, we define the biological landscapes of neoplastic cell extrinsic environment, branded the TME, discuss therapeutic resistance that engages multiple stromal cell types, and present clinical challenges lying ahead which may be well taken by implementing effective strategies to deliver personalized cancer therapy.

Tumors evolve in a complex, dynamic, and functionally multifaceted microenvironment, which they rely upon for sustained growth, invasion, and metastasis. Unlike cancer cells, stromal populations within the TME are genetically stable, and thus represent an attractive therapeutic target with minimal risk of treatment resistance and disease re- lapse. TME-oriented research is increasingly encouraged and advocated, including the endeavors made in basic, clinical, and translational medicine. In such an exciting era of TME biology, experimental data have led to new scientific concepts and identified novel therapeutic targets to control the TME-related pathologies.

However, there are not only major advances but daunting challenges, the latter including how to uncover and restrain susceptible nodes in the structurally complex and functionally intertwined TME system. Given that key signaling pathways frequently cross-talk and mutually interact in an intricate network, insights into how to solve the tortuous maze in a wider landscape and how tumor type-specific TMEs may respond differently to current standard-of-care therapies remain as important issues to tackle with intelligence. Fortunately, with the wealth of data accumulated so far, we now have a roadmap to con- vert these challenges into opportunities. For instance, when defining predictive markers that will eventually aid in the selection of patients who most likely benefit from intervention, analysis based on the entire TME is an essential step of utmost importance to determine specific therapies to employ [17,103,104]. To this end, gene expression profiling has been proposed as predictive for response to a given therapy, while in the coming years a panel of markers will become available to achieve the predicted goal.

More importantly, cancer cell-directed agents should be combined with the TME-targeting therapies as it is increasingly clear that stromal cells modulate the efficacy of a broad range of standard chemotherapies and targeted agents. Last but not least, manipulating a dysfunctional TME is critical and will yield striking results in cancer prevention, pathological control, and disease remission, as evidenced by the recent success of multiple pilot trials in clinical oncology.

Source:
Chen et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Medicine (2015) 13:45 DOI 10.1186/s12916-015-0278-7

References:
1. Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell. 2005;7:513–20.
2. Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6:254ra125.
3. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014;514:54–8.
4. Mroue R, Bissell MJ. Three-dimensional cultures of mouse mammary epithelial cells. Methods Mol Biol. 2013;945:221–50.
5. Chen F, Qi X, Qian M, Dai Y, Sun Y. Tackling the tumor microenvironment: what challenge does it pose to anticancer therapies? Protein Cell. 2014;5:816–26.
6. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–54.
7. Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012;9:542–8.
17. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.
103. Bellmunt J, Pons F, Orsola A. Molecular determinants of response to cisplatin-based neoadjuvant chemotherapy. Curr Opin Urol. 2013;23:466–71.
104. Tam V, Hooker CM, Molena D, Hulbert A, Lee B, Kleinberg L, et al. Clinical response to neoadjuvant therapy to predict success of adjuvant chemotherapy for esophageal adenocarcinoma. J Clin Oncol. 2014;32(Suppl 3; abstr 137).


What I Believe is Important in Integrative Oncology (IO):

By reviewing various published research articles we know that over 50% of women with breast cancer as well as significant percentage of other cancer patients, use some form of complementary alternative medicine (CAM) along side bio-medical oncology. Patients use CAM because they want to feel they have some control over their cancer, although there is not always ample evidence to support its use. There is not, nor will there likely be RCTs or Phase IV clinical trials on any of the medicines due to real financial limitations. Most botanicals used in cancer treatment are safe and effective and there is some good research on drug-herb interactions as well. There is a long history of use as well as extensive use in Hospitals in many countries, although primarily in China. Some oncologist limit patient use of these substances but patient seek them out anyway.

While academic research using RCTs are the bedrock of evidence-based medicine, the whole area of complementary oncology is peripheral to mainstream paradigms, yet patient will and do seek them out whether their oncologist knows they do so. I believe the use of botanicals in conjunction with bio-medical oncology practice is the wave of the future and needs to be codified and implemented in a formal fashion. Traditional Chinese Medicine is part of Systems Biology approach and operates outside but alongside a conventional reductionist, Newtonian research paradigm. Metabolomics, genomics as well as the whole area of Omics research needs to be applied to complementary oncology and we need to move medical science from its Newtonian/Modernism underpinnings to where other sciences have arrived. We need to deconstruct medicine.

Research, where a systems approach is used means each patient is viewed as unique and their treatment is unique to their needs; We treat the patient not their disease. TCM and other traditional medicines are ancient systems medicine, where diagnosis by traditional means determined the protocol used and this is already highly quantified. Its limit is the lack of integration between the language used to understand the "Pattern" and current bio-medical diagnostic language but I believe this is now possible to bridge this gap. TCM concepts are sound but the language associated with these concepts need translating into a modern idiom. Diagnostic techniques also need updating, using modern approaches to confirm traditional understandings of "Pattern". In TCM, "pattern" (证, pinyin: zhèng) refers to a "pattern of disharmony" or "functional disturbance" within the functional concept the TCM model of the body. It is not the disease itself but the underlying dynamics by which the disease arose.

I believe research protocols themselves need re-evaluation and finding ways to create a systems biology approach, which focuses on complex interactions within biological systems, using a holistic approach (holism instead of the more traditional reductionism). Current developments using circulating tumour cells, where individual medicinals can be matched to the patient's cancer cells is one way forward. Another is to look at and regulate various pathways such as VEGF, mTOR etc in rather than the tumour type.

I believe the current scientific approach has gone by its use-by-date and we need to revision it, create a new, yet valid medical approach, which will inevitably benefit the patient not the oncology industry. Yes, good integrative approaches to cancer will not only be effective but cheaper.


FOLFOX 4 Combined with Herbal Medicine for Advanced Colorectal Cancer: A Systematic Review

A study by Chen et al., found that herbal medicine had a major positive effect on patients with advanced colorectal cancer in several key areas. This systematic review evaluates the clinical evidence for the addition of herbal medicines (HMs) to FOLFOX 4 chemotherapy for advanced colorectal cancer (ACRC) in terms of tumor response rate (tRR), survival, quality of life (QoL) and reduction in adverse events (AEs). Seven electronic databases were searched for randomized controlled trials (RCTs) of FOLFOX4 combined with HMs compared to FOLFOX4 alone. Outcome data for 13 randomized controlled trials were analysed using Review Manager 5.1. Risk of bias for objective outcomes including tumor response and survival was judged as low. Publication bias was not evident.

The meta-analyses found the addition of HMs improved tRR (RR 1.25, 95%CI 1.06-1.47, I2  = 0%), one year survival (RR 1.51, 95%CI 1.19-1.90, I2  = 0%) and quality of life in terms of Karnofsky Performance Status (KPS) gained (RR 1.84, 95%CI 1.54-2.19, I2  = 0%); alleviated grade 3 and 4 chemotherapy-related AEs for neutropenia (RR 0.33, 95%CI 0.18-0.60, I2  = 0%), nausea and vomiting (RR 0.34, 95%CI 0.17-0.67, I2  = 0%) and neurotoxicity (RR 0.39, 95%CI 0.15-1.00, I2  = 0%), compared to FOLFOX4 alone.

The most frequently used herbs were Astragalus membranaceus, Panax ginseng, Atractylodes macrocephala, Poria cocos, Coix lachryma-jobi and Sophora flavescens. In experimental studies, each of these herbs has shown actions that could have contributed to improved tumor response.

Source
Chen M, May BH, Zhou IW, Xue CC, Zhang AL. (2013) FOLFOX 4 Combined with Herbal Medicine for Advanced Colorectal Cancer: A Systematic Review. Phytother Res. 2013 Dec 17. doi: 10.1002/ptr.5092.



Prostate Cancer Metastasis

Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. It was also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, Hsu et al, (2013) investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Their results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser(727) (p-Ser(727)-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. 

They further show that the nuclear distribution of p-Ser(727)-STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser(727)-STAT3 and therefore upregulate AR protein stability and transactivation. 

Correspondingly, clinical evidence shows that the level of p-Ser(727)-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser(727) phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells. 

Cdc25A inhibitory activity and antitumor activity are detected in the extracts isolated from three Chinese medicinal herbs Agrimona pilosa; Herba solani lyrati; 
Galla chinesis. Yang et al, (2005) found three extracts isolated from Chinese medicinal herbs have potential inhibitory activity of Cdc25 phosphatase using a highly specific mechanism-based screen assay for antimitotic drug discovery. The extracts from three Chinese medicinal herbs, Agrimona pilosa, Galla chinesis and Herba solani lyrati as potent Cdc25 inhibitors through bio-screening assay. 

Agrimona pilosa (Xian He Cao) has been used in traditional Chinese remedy against parasites, including taenia, malaria plasmodia, schistosomomas and vaginal trichomonas. Its leaves are rich in vitamin K and are used to promote blood clotting and control bleeding stop bleeding and to prevent infection. Galla chinensis is used for chronic cough and diarrhea, spontaneous emission and perspiration as well as night sweat. 

These three Chinese medicinal herbs were reported effective for treatment of cancer patients. However, the active constituents of them against tumor are largely unknown. Ellagic acid, a phenolic compound, the active ingredient extracted from Galla chinensis, is known to be effective against cancer of the rectum and colon, esophagus, liver, lung, tongue and skin. Ellagic acid has been demonstrated to inhibit tumor growth in animal models and clinical studies (Constantinou et al., 1995). Studies have shown that treatment of Ellagic acid leads to cell cycle arrest within 48 h and apoptosis within 72 h for cancer cells (Losso et al., 2004; Mertens-Talcott and Percival, 2005). 
Whether Ellagic acid or other active constituents could inhibit Cdc25 phosphatase activity is largely unknown at present. Therefore, it is necessary in future to isolate the active compounds from the extracts of these Chinese medicinal herbs and to determine the Cdc25 inhibitory effect of these active compounds. On the other hand, in our investigation a large amount of apoptosis induced by three extracts has been detected by flow cytometry, of which the molecular mechanisms also need to clarify (Kim et al., 2003).

Sources
Constantinou A, Stoner GD, Mehta R, Rao K, Runyan C, Moon R. The dietary anticancer agent ellagic acid is a potent inhibitor of DNA topoisomerases in vitro. Nutr Cancer. 1995;23:121–130. 
Hsu FN, Chen MC, Lin KC, Peng YT, et al. (2013) Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells. Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E975-86. doi: 10.1152/ajpendo.00615.2012. 
Kim HJ, Kang SK, Mun JY, Chun YJ, Choi KH, Kim MY. Involvement of Akt in mitochondria-dependent apoptosis induced by a Cdc25 phosphatase inhibitor naphthoquinone analog. FEBS Lett. 2003;555:217–222. 
Losso JN, Bansode RR, Trappey A, Bawadi HA, Truax R. In vitro anti-proliferative activities of ellagic acid. J Nutr Biochem. 2004;15:672–678.
Mertens-Talcott SU, Percival SS. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett. 2005;218:141–151.
Yang H, Zheng S, Meijer L, et al. (2005) Screening the active constituents of Chinese medicinal herbs as potent inhibitors of Cdc25 tyrosine phosphatase, an activator of the mitosis-inducing p34cdc2 kinase. J Zhejiang Univ Sci B. 2005 July; 6(7): 656–663. 2005 June 23. doi:  10.1631/jzus.2005.B0656


The Art of Combining

The art of medicine has two aspects, correct diagnosis and correct prescribing. The next most critical factor is how to combine various compounds to enhance treatment. Wrong combinations can undo a good treatment while good combining enhances and creates an effect greater than the sum of the parts.

Most therapeutic products combine well with many antioxidants such as resveratrol, EGCG, CoQ10, SeaBuckthorn oil, Alpha Lipoic Acid or curcumin. The primary vitamin antioxidants like vitamin A, E and C are also combined, as is selenium. I generally suggest cycling antioxidants to enhance their individual characteristics ie resveratrol from 1 to 14 days, introducing another such as EGCG at the 7th day continuing until the 21 st day and introducing a third antioxidant like CoQ10 at day 14, etc.

R Lipoic acid and Acetyl L-Carnitine can be used continually as R Lipoic acid is a bi-directional antioxidant which recycles other antioxidants and acetyl L-Carnitine is a stimulant to the cell's mitochondria.

Curcumin and Quercetin is particular useful as a mild general antiinflammatory for those consuming alcohol and grilled meats and/or fried foods. Inflammation control substances such as boswellic acid, berberine from Coptidis and tetrandrine and fangchinoline from Stephania are useful for chronic inflammatory conditions due to environmental toxicity and can be used with other more specific compounds.

A regular use of a de-tox formula is important. As I repeatedly say de-tox the gut first, them the liver. Controlling lectin is an important adjunct to nearly every therapeutic regime from weight loss to cancer to chronic degenerative diseases. Don't forget to follow up with a pre-biotic and a pro-biotic to enhance good gut flora. Don't forget SeaBuckthorn Oil repairs sensitive gut, respiratory and urinary tissues.

Remember, when combining various compounds it is a good idea to reduce dosages about 20 to 30% to factor the synergistic effects. The cycling of a number of antioxidants gives better results than continuous use of just a few compounds. Remember, combining is one of the highest arts in medical prescribing and you will get better results, faster.

Cancer Cells are the Terrorists of the Body

Cancer is a disease of the cell, a cell that is out of control, but it not only the single-cell but also the community of cells that creates tumours. Cells are like people; they are born with a purpose but in the beginning they all are pretty much the same. They mature and take on the characteristics of their function and then they age and die. When things go wrong, the body like society has a mechanism to bring things back into harmony. The body, like society runs on rules and tolerates only very small infractions. These small infractions are met with a process called sickness or immune response. When the body, like society is overwhelmed because of poisons, stress, poor nutrition and a toxic environment the order breaks down and criminal cells become immune to the rules and run wild. This is cancer. When they go very wrong they go wrong in a number of clearly understood ways; they become unstable, they inhibit proper and orderly behaviour and they loose control of their internal communication process. If this all sounds a bit like human criminal behaviour you're not wrong. Next these rogue cells cut themselves off from their community and isolate them-selves, they rapidly reproduce and create their own blood supply and then they invade surrounding tissues (healthy cells). Lastly they create 'camouflage' and evade the police (immune system).

Also, it is important to understand that these cells don't act alone but are created in a toxic body environment that allows them to flourish. This analogy indicates that cells and society have a great deal in common. In a healthy culture citizens behave themselves, co-operate with each other and do their jobs in an orderly fashion. We are born, mature and die all within the laws and codes of the society. When we break the rules we are punished. Likewise every cell has a function and must obey the laws of biology. When they fail at that function, they are punished. The surrounding cells kill cells that go rogue or they are told to commit suicide, this is called apoptosis. It keeps the body healthy and functioning.

Disease Origins

Traditionally disease is traditionally divided into two categories; Exogenous or externally caused and endogenous or internally caused. For most of human history, externally caused diseases were the primary cause of death and debilitation. Bacteria, virus, poisons and parasites were the factors killing people at an early age. With increases in public health, sanitation and modern medicine these factors are in decline. What arises today with our longer life expectancy are diseases of endogenous origin, the breakdown of organs and systems due to internal causes. When we look at internal disease patterns we can roughly see two distinct conditions. One we can call degeneration, which is due to deficiency or what commonly occurs as we age; the immune, nervous and organ systems weaken and collapse. The other is called chronic systemic inflammatory diseases (CSID). CSID are often seen as autoimmune diseases but are also present in a diverse range of conditions such as benign prostatic hypertrophy (BPH), arterial plaque as seen in cardiovascular disease (CVD) , measured by C-Reactive Protein and even in insulin resistance and Type 2 diabetes. The two states are of course related. cancer arises from the relationship of these two internal disease states; the breakdown of systems integrity and the arising of chronic inflammation.

The Cancer Cure:

Conventional Tumour Reduction Therapies (CTRT); Chemo, Radiotherapy and Surgery have not reduced cancer mortality over the last 30 years and in fact age-adjusted figures indicate a 6% increase. Heart disease has had a 240% decrease and cerebrovascular a 317% decrease since 1950. Also, a reduction in smoking and early diagnosis has not altered cancer mortality rates. [1] There are indications of a reduction in breast cancer since 2002, however many researchers speculate this is the result of the lesser use of HRT in older women and a subsequent drop in breast examinations in that group. Recently, in the US George Bush declared a 1% drop in cancer incidence reports but many outside the National Cancer Institute suggest a under reporting by the Veterans Administration in some 28 States may have affected the results. Figures in Australia from 'the Cancer Council'

How does cancer in Australia compared with other countries?

Randomised Controlled Trials (RCT) on CTRT was reported in 1.6% of all surgery articles, 3% on radiotherapy and 4.6% on chemotherapy. Overall controlled survival rate studies were not measured in nearly 97% of all articles listed in PubMed between 1996 and 2001 [1].

In 2002 91% of cancer patients in the USA use TM-CAM measures [1]. In another survey up to 64% of patients surveyed used TM-CAM [2]

Is there a cure for cancer?
It would seem many researchers, both in conventional medicine and complimentary medicine are working for such a solution but at this time no complete cure exists for solid tumours - though this doesn't mean there aren't useful approaches to cancer treatment. This also does not mean many patient aren't in complete remission after the 5 years suggested as cure. What I suggest is there is no universal cancer cure that works all the time for everyone. Five years ago, and even 2 years ago mainstream oncologists were dismissive of TM-CAM, however since that time an increasing number are incorporating TM-CAM compounds into conventional medical treatments. As stated above, up to 91% of cancer sufferers in the US use TM-CAM. Anecdotal, clinical information as well as published research suggests TM-CAM therapies increase quality of life [3,4], enhance conventional treatments [5] and are becoming part of the mainstream protocol.

Many Causes, Many Solutions
There is no single cause for cancer although ageing seems universal if one assumes the DNA mutation theory of cancer. But other researchers suggest improper development of stem cells [6], while still others suggest a breakdown of the immune system. There are many legitimate theories. The research continues and we at CANCER DIALOGUES will bring as much to you as we are able to publish. In the future we will be publishing a fully searchable CD with the latest published and referenced research material on CAM compounds.

References

1. Complementary Oncology. Beuth, Josef and Moss, Ralph. Thieme 2002, 2006
2. Cancer. Volume 83, Issue 4, Pages 777 - 782
3. Oncol Nurs Forum. 2000 May;27(4):623-30.
4. Journal of Clinical Oncology, Vol 19, Issue 9 (May), 2001: 2439-2448.
5. Journal of Clinical Oncology, Vol 18, Issue 13 (July), 2000: 2505-2514 5. Mol cancer Ther. 2003;2:855-862
6. Nature. 21 September 2007; | doi:10.1038/news070917-11.