Body Terrain and the Tumor Microenvironment

Cancer cells do not act alone. They enlist the body’s normal cells, molecules, and blood vessels in their efforts to survive, metastasize, and acquire drug resistance.

Memorial Sloan Kettering Cancer Center¹

Key Points

The recognition of the whole body's role and interactivity with cancer cells is an ancient concept that is currently gaining traction in mainstream medicine.
Malignant and nonmalignant cells interact to create the tumor microenvironment.
Cells in the tumor microenvironment play a key role in cancer’s development, spread and response to treatment.
Modifying your body terrain to make it inhospitable to cancer is one of the most important actions you can take. However, these actions alone are not enough to control or cure cancer.

Definitions

Terrain: from the French word terrein—ground or land, especially their physical features. In integrative medicine circles (especially in Europe) terrain denotes the physical features and state of a person’s body and the influence of that state on health and disease prevention. “It is the sum total of diet, lifestyle, metabolism, environmental exposures and stress.”²
Tumor Microenvironment (TME): “The normal cells, molecules, and blood vessels that surround and feed a tumor cell. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads.”³

“The study of terrain is beginning to gain traction in mainstream cancer research.”⁴ However, the concept is not new: traditional Chinese medicine (TCM) has viewed terrain as important for millennia. Viewing cancer as a systemic disease and the tumor as a symptom of that disease, TCM considers that to heal the disease, the underlying constitution must be altered.

Integrative oncologist and BCCT advisor Keith Block, MD, more specifically focuses on the “biochemical terrain” and whether or not that biochemistry is balanced or disrupted and therefore inhospitable or hospitable to cancer.⁵

For the purposes of this summary, we consider the terrain as the internal environment of the human host and the tumor microenvironment existing within and influenced by the host’s terrain.

Importance of the Microenvironment

In recent years, we’ve had to let go of the notion that cancer is just a mass of malignant cells or simply a disease of aberrant genes—if so, we would have long ago succeeded in eliminating or curing cancer by removing or destroying cells or targeting genetic mutations. Rather, cancers are “complex ‘rogue’ organs, to which many other cells are recruited and can be corrupted by the transformed cells.”⁶

Malignant and nonmalignant cells interact to create the tumor microenvironment (TME). “The nonmalignant cells of the TME have dynamic and often tumor-promoting functions at all stages of carcinogenesis.”⁷ More simply put: “Cancer is a complex mixture of cancer cells, normal blood cells, tissue and immune cells. Tumor cells themselves alter the microenvironment to secrete things that help tumors grow.”⁸

Highlighted Video

BCCT Senior Researcher Laura Pole, RN, MSN, OCNS, explains the importance of tending your terrain and tumor microenvironment.

When it comes to understanding the tumor microenvironment and how to create a body in which cancer can neither thrive nor survive, a few gardening concepts provide a good analogy. Cancer is the seed and the body is the soil that cancer might try to use as a growth medium. Your terrain is the body’s/soil’s internal environment. Let's think of the cancer seed as one from a thorny or even poisonous weed—not one we want growing in our soil/body.

Same Soil, Different Outcome?

“Cancer is not an isolated group of errant cells waiting passively to be annihilated by a wonder drug. . . Cancer does not present a single target for a magic bullet; a tumor is merely the most obvious symptom of an altered, unbalanced system. . .And that’s why both the new targeted therapies and the older weapons of surgery, radiation and old-line chemotherapy so often fail to prevent the spread or recurrence of the disease. . . They neither pick up renegade cancer cells, strengthen the body’s biological balance, nor reach all of the underlying molecular accidents that initiated cancer in the first place. . . As a result, even if the original tumor is gone, this biological imbalance creates an environment for cancer to recur: tumor cells use the body’s healthy resources to grow and multiply.”⁹

Our Soil, Ourselves

We’ve tended to focus on the cancer, but its host tissue—the soil, rather than the seed—could help us predict the danger the cancer poses. If we look at the soil, as well as the seed, “it would return us to the true meaning of ‘holistic’—to take the body, the organism, its anatomy, its physiology—this infuriatingly intricate web—as a whole . . .It would help us understand when you have cancer and when cancer has you. It would encourage doctors to ask not just what you have but what you are.”¹⁰

This profound quote from Dr. Mukherjee, author of The Emperor of All Maladies, provides a remarkable insight: If we come to know a person’s soil, their terrain, we can understand why cancer could take hold in them in the first place, predict how dangerous that cancer is to the patient if things don’t change, and then create an individualized treatment approach that targets the seed while it tends the soil.

Tending Your Terrain

Many of our therapy summaries include references to tending the terrain, the seed and soil, the tumor microenvironment and making the terrain inhospitable to cancer. Indeed, many of the healing practices that are part of a healthy lifestyle contribute to making the body inhospitable to cancer, and therein may lie their value in helping delay or reduce risks of cancer recurrence. In addition, these practices may also stave off other conditions or illnesses typically spawned from treatment toxicity, such as cardiotoxicity.

Modifying the Terrain

Naturopathic oncologist and BCCT advisor Lise Alschuler, ND, FABNO, and co-author Karolyn Gazella write about creating a body that cancer doesn’t like. They describe five key pathways that have the greatest impact on whether we are healthy or become sick:

The immune system
Inflammation
Hormonal balance
Insulin resistance
Digestion and detoxification

They go on to describe five core strategies and corresponding action steps that positively influence the key pathways (BCCT's corresponding healing practices are noted in parentheses):

Enhance your spirit (Exploring What Matters Now)
Let’s move (Moving More)
Enrich your diet (Eating Well)
Utilize dietary supplements
Create rejuvenation

They explain that through these strategies we train our cells to retain their optimal resistance and effectiveness over cancer while also creating an environment that is inhospitable to cancer growth. First, the authors describe how cancer develops. Although cancer is characterized as a disease of genetic mutations, most of them don’t start with inherited gene mutations. Rather, the mutations are a result of mutated gene expression that develops over time.

“Cancer promoter genes are turned on, while cell repair and cancer-suppressor genes are switched off. This aberrant gene expression changes cell behavior, causing cells to divide too quickly, to spread into the surrounding tissue and to make proteins that call in new blood vessels. These changes, in turn, sustain the aberrant cells while maintaining a tissue environment that supports their continued growth. . . ultimately forming a cancerous tumor, or in the case of cancers of the blood, they circulate in malignant cell clusters. . . . Our lifestyle actually sends molecular messages to cell membranes that are then translated inside the cell and delivered to its very core, the nucleus, the home of DNA. There, these molecular signals interact with the DNA and become genetic switches that turn genes on and off. The on-and-off pattern determines the behavior of the cell and will ultimately move the cell toward improved function and health, or toward deviant behavior and disease.”¹³

In his book, Life over Cancer, Dr. Keith Block devotes an entire section on boosting your biology through using the healing power of terrain. “Your internal biochemistry can either nourish cancer cells or send them into molecular oblivion.”¹⁴ Block goes on to explain that the biochemical terrain is your body’s internal chemical environment, and it plays a vital role in “determining whether a tumor will regain its foothold after treatment, metastasizing to distant sites, or whether it will stay where it is without posing any threat. The internal biochemistry influences the microenvironment immediately surrounding the cancer cells. An inhospitable environment impacts the disease.”¹⁵ Similar to Alschuler and Gazella’s pathways, Block writes that addressing six “defining features” of your biochemical terrain is necessary. Cancer thrives on each of these when out of balance:

Oxidation
Inflammation
Immunity
Blood coagulation
Glycemia (blood sugar)
Stress chemistry and biorhythms

Inflammation: An Example

The immune response is a key terrain factor related to cancer growth and spread.¹⁶ While we want an active immune response against tumors, we also do not want an inflamed state. Inflammation is associated with the development and malignant progression of most cancers..¹⁷

Studies and meta-analyses have found that those with the highest pre-diagnostic levels of C-reactive protein (CRP)—a marker of chronic inflammation—have higher rates of cancer than those with lower levels:

Breast cancer¹⁸
Colorectal cancer risk¹⁹ and mortality²⁰
Kidney cancer (Renal cell carcinoma)²¹
Lung cancer and all cancers combined²²
Prostate cancer²³
Urologic cancers: bladder, penile and upper tract urothelial carcinoma²⁴

Moreover, “changes in post-treatment CRP serum levels have also shown promise in determining survival.”²⁵ Reducing C-reactive protein even after diagnosis and treatment can enhance survival.

Addressing Inflammation

Michael Irwin, MD, of the UCLA Department of Psychiatry and Biobehavioral Sciences prefers not to use anti-inflammatory drugs to reduce inflammation in cancer patients due to multiple side effects. He has researched several mind-body approaches and found these are useful in improving or reversing insomnia and subsequently improving inflammatory markers:

Other symptoms such as depression and fatigue also improved.²⁶

Blood Sugar and Insulin: Another Example

Other studies and reviews investigating blood sugar and insulin find a relationship with cancer risk and progression:

All cancer²⁷
Breast cancer²⁸
Colorectal cancer²⁹
Endometrial cancer³⁰
Melanoma (lower risk)³¹
Pancreatic cancer³²
Prostate cancer risk (both higher and lower) and mortality³³

Balancing each of the above six terrain features, according to Block, helps to deal with the five major challenges of having cancer:

Reducing tumor growth and spread
Reducing tumor bulk and improving treatment response
Tolerating conventional treatment
Optimizing daily functioning
Reducing the risk of life-threatening complications

Dr. Block describes how to determine which aspects of your internal terrain you most need to target, providing protocols for addressing each terrain feature as well as a general protocol for broad-spectrum terrain support supplementation.³⁴

The Hallmarks of Cancer and the Tumor Microenvironment

Scientists Douglas Hanahan and Robert Weinberg created a framework called the Hallmarks of Cancer. These hallmarks are the biological capabilities that cancer cells acquire as they go through a multi-step process of developing into tumors.³⁵

The following list of hallmarks is “sequenced roughly in the order in which these capabilities are acquired by most cancers.”³⁶

Genomic instability: Unstable DNA helps cancer cells “acquire a selective advantage over neighboring cells, enabling outgrowth and dominance in the tissue microenvironment”, especially important in tumor initiation and promotion.³⁷
Sustained proliferative signaling: Cancer cells become self-sufficient and able to grow uncontrollably.
Evasion of anti-growth signaling (evading growth suppressors): Cancer cells no longer respond to antigrowth signals.
Resisting apoptosis (programmed cell death): Cancer cells are able to circumvent the cycle of programmed cell death (apoptosis). Normal cells submit to apoptosis when they are no longer needed or might be harmful to the body.
Replicative immortality: No limits exist on the cancer cell to reproduce over and over.
Deregulated metabolism (cellular energetics): Cancer cells shift from producing energy in the mitochondria to inefficiently fermenting glucose within the cell itself.
Tumor-promoting inflammation: The chronic inflammation microenvironment is associated with cancer formation, growth and transformation as well as apoptosis evasion, survival, invasion, angiogenesis and metastasis.³⁸
Immune system evasion (avoiding immune destruction): Cancers evade immune attack through several mechanisms.
Tumor microenvironment: At this point, the tumor is primed to use the microenvironment to grow and spread.
Inducing angiogenesis: Cancer uses normal cells to create a blood supply to bring in nutrients and remove waste.
Activating tissue invasion and metastasis: Cancer’s most deadly ability arises, spreading to other organs.

Except for the few inherited cancers derived from a genetic defect (germline mutation), most cancers start off as normal cells that eventually acquire alterations (mutations) in their DNA and essentially “learn” or acquire biological abilities that promote their growth, survival and spread.

These Hallmarks of Cancer are accepted by scientists and clinicians as the foundation for understanding the biology of cancer. Furthermore, many of today’s cancer treatments are designed to target one or more of the hallmarks of cancer. For example, agents such as Bevacizumab (Avastin) and Sunitinib (Sutent) inhibit angiogenesis.³⁹

The hallmarks are focused specifically on the biology and behavior of cells, but the tumor microenvironment is intertwined with the ability of cancer to acquire and maintain the biological abilities to seed, grow, survive and spread. Under the right conditions, the cancer can hijack the microenvironment for its own use.

Consideration of the microenvironment is so vital that an international task force of 180 scientists participating in the Halifax Project suggested that the tumor microenvironment be added as a Hallmark of Cancer. The Halifax project was concerned that our current model of cancer care is becoming completely out of reach for many people in the world. Specifically, they were honing in on the problems of conventional targeted therapies (such as Keytruda, Avastin, and so on.):

High costs
Short relapse-free period
Dose-limiting and combination-limiting toxicities

In addition, they emphasized that there’s not just one “weed in the forest”, and one drug alone won’t knock out all the weeds. Finally, most tumors have some cells that don’t have the intended target for the targeted drugs; so about 90 percent of remaining cells will still flourish.

From this basis, the primary purpose of the Halifax Project was to “explore the concept of a low-toxicity ‘broad-spectrum’ therapeutic approach that could simultaneously target many key pathways and mechanisms.”⁴⁰ Teams looked at each cancer hallmark as well as the tumor microenvironment and nominated 74 high-priority targets in a wide range that could be modified to improve patient outcomes. They then suggested low-toxicity therapeutic approaches (many were phytochemicals) for each target.

The project produced suggestions primarily for research program development, not clinical guidelines. However, the authors of a report on the project note that “lifestyle therapies appear to affect multiple molecular targets and to improve the health of cancer patients in a variety of ways, and integrative lifestyle modifications should be assessed as a health-promoting foundation for use of broad-spectrum therapeutics . . . The positive implications of dietary therapies for improvement of the metabolic hallmarks of inflammation, dysregulated metabolism, genomic instability and immune system evasion should be kept in mind. . . Clinicians choosing to use natural product supplements should attend to product quality and be familiar with advances in the formulation of poorly absorbed polyphenols and other phytochemicals.”⁴¹ In sum, both doctors and patients should consider lifestyle changes, and especially eating well and using quality supplements wisely, as the foundation of therapy.

Some participants in the Halifax project suggest that if patients wish to use the broad spectrum approach outlined by the project, they consider working with clinicians doing leading-edge work (some of whom participated in the Halifax Project, such as Keith Block).

Sources of information on such clinical approaches:

Abrams DI, Weil AT. Integrative Oncology. 2nd Edition. New York, NY: Oxford University Press. 2014. See chapter 3, Molecular Targets of Botanicals Used for Chemoprevention.
Alschuler LN, Gazella KA. The Definitive Guide to Thriving after Cancer. Berkeley, California: Ten Speed Press. 2013.
Block KI. Life Over Cancer: The Block Center Program for Integrative Cancer Treatment. New York: Bantam Dell. 2009.
Chang R. Beyond the Magic Bullet: The Anti-Cancer Cocktail. New York: Square One Publishers. 2012.
McKinney N. Naturopathic Oncology, 3rd Edition. Victoria, BC, Canada: Liaison Press. 2016. See chapters on integrative care for specific cancers. Each of these chapters lists the targets of therapy and coinciding complementary approaches.
Will LaValley, MD:
- LaValley MD Protocols
- The Cancer Information Database for Information about Integrative Cancer Treatments: A Special Interview with Dr. William LaValley
- Upcoming book: Molecular Integrative Oncology

The 7 Healing Practices: Modifying the Terrain

The 7 Healing Practices can actually modify many of the terrain factors that nourish the tumor microenvironment.

Eating Well

Eating well affects many of the factors defining one’s terrain. Dr. Keith Block reviews "terrain offenders" in his book Life Over Cancer. Some dietary offenders:⁴²

Oxidation is increased by consuming alcohol, unhealthy fats, high levels of dietary iron, and eating more calories than you burn.
Inflammation is increased by alcohol consumption, unhealthy dietary fats and carbohydrates, and unhealthy cooking methods.
Immune surveillance is hampered by alcohol consumption, poor nutrition, unhealthy dietary fats, dairy foods, and iron-rich foods.
Glycemia is tipped toward elevated blood sugar by eating too much, especially high glycemic-index foods and inflammation-producing foods, and by eating infrequent large meals.
Stress biochemistry is thrown off balance by caffeine, alcohol, a low-carbohydrate and high-fat or high-protein diet, eating a high ratio of omega-6 to omega-3 fats, and overeating.

Oxidation is a good example of how eating habits and terrain are related. Oxidation creates free radicals that disable tumor-suppressor genes and/or activate tumor promoting genes (oncogenes). Oxidative stress can raise the malignant capabilities of a tumor.⁴³

Some foods are a source of oxidation, including too much fat, and especially saturated fats. Eating saturated fat, monounsaturated fat and animal fat is modestly associated with breast cancer risk and mortality,⁴⁴ and a small study found that women with breast cancer who ate higher levels of dietary fat had more damaged DNA in their tumors compared to women on a low-fat regimen.⁴⁵

Favor eating foods high in antioxidants:

Colorful fruits and vegetables
Barley, millet and oats
Wild-caught salmon
Legumes, especially soy, pinto, black, broad, kidney and small red beans
Nuts and nut oils as well as extra virgin olive oil
Tea
Spices: oregano, dill, garlic, ginger, rosemary, cloves, sage, cumin, paprika

Alcohol consumption, another source of oxidative stress, is also associated with a higher risk of breast cancer.⁴⁶

The ketogenic diet is being studied as a possible means to affect cancer’s ability to co-opt the TME to support its altered energy metabolism. See our Ketogenic Diet summary.

For more information about eating well to support a healthy biochemical terrain, see our Eating Well summary.

Moving More

Managing Stress

Sleeping Well

Highlighted Videos

BCCT advisor Brian Bouch, MD, explains the importance of toxicity and genes in integrative cancer care, plus a functional medicine approach to diagnosis and care.

BCCT advisorBrian Bouch, MD, explains how to boost immunity before starting conventional cancer treatments.

Sharing Love and Support

Exploring What Matters Now

Those of us who have worked for years guiding people with cancer and carefully observing what really matters agree that finding joy, finding meaning, or finding purpose seems to be the essence of living well (and in many cases, living longer than the doctors predicted).

Indeed, every one of BCCT’s integrative oncologist advisors include care of the spirit in their integrative protocols. As Keith Block writes, “Every possible factor influencing the progression of cancer should be explored when you are fighting for your survival. I have seen time after time the difference it [mind-spirit care] makes.”⁵⁶ Some evidence indicates pleasant emotions can produce a physiological response to that can impact immune function, hormonal balance and insulin resistance—three of the five key pathways of disease mentioned above. For example, a 2006 study “revealed that an increase in secretory immunoglobulin A and a decrease in salivary cortisol were induced by pleasant emotions."⁵⁷

Accurately and scientifically measuring the biological effects of meaning or purpose on the tumor microenvironment is difficult, but early evidence shows a relationship between mind/spirit and survival. Researchers have postulated that a distinct personality type (sometimes called “type C”) is possibly at greater risk of developing certain cancers. This personality type is marked by being passive and submissive and minimizing or denying a person’s authentic spirit. These adaptive personality characteristics may favor the development or progression of disease. If so, then working to address these adaptive characteristics may contribute to healing.

Small studies involving people with incurable or metastasized cancer have investigated this line of thinking. Two small studies showed significant increases in survival with psychotherapy. The first correlated extended survival among those who scored higher on these scales:⁵⁸

Ability to act and change
Willingness to initiate change
Application to self-help work
Relationships with others
Quality of experience

In the second study, longer-term survivors displayed a much higher degree of early involvement in their psychological self-help than did most of their nonsurviving peers. The researchers found these common qualities among the survivors:

Authenticity, a clear understanding of what was important in one's life
Autonomy, the perceived freedom to shape life around what was valued
Acceptance, a perceived change in mental state to enhanced self-esteem, greater tolerance for and emotional closeness to others, and an affective experience described as more peaceful and joyous.

The authors hypothesize “to the extent that the progression of cancer, or other chronic disease, is favored by a distorted psychological adaptation such as type C, healing may be assisted by a reversal of that adaptation—in the case of cancer, toward greater authenticity of thought and action.”⁵⁹

Though mind and spirit will not directly attack cancer, Block asserts that they exert potent indirect influence on the growth and spread of cancer by affecting your internal biochemistry, including molecular factors, and the state of your immune system.⁶⁰

Meanwhile, anyone caring for and paying attention to the whole person with cancer knows that helping people find meaning and joy might very well be the thread that holds all the swatches together.

For more information, see our Exploring What Matters Now summary.

Terrain Is Important but Not a Panacea

Anticancer Lifestyle Program

Using expert videos, animation, text and interactives, the Change Module of the Anticancer Lifestyle Program introduces you to the course, and help you make lasting lifestyle changes that will decrease inflammation and enhance your immune system’s ability to fight disease.

This course is offered on a “pay-what-you-can” basis for 90-day access to all course modules.

Both cancer treatment to address the tumor and terrain modification to make the body less hospitable to recurrence are called for.

Modifying your biochemical terrain, alone, is not enough to control or cure cancer. On the other hand, conventional cancer treatments alone will not consistently keep the cancer from coming back.⁶¹ Generally, both cancer treatment to address the tumor and terrain modification to make the body less hospitable to recurrence are called for. Over and over again, we return to the point that an integrative approach may provide the best chance of exploiting cancer’s weaknesses.

Written by Laura Pole, RN, MSN, OCNS, and Nancy Hepp, MS; most recent update on November 3, 2020.

View All References

More Information

Articles

Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. Journal of Cell Science. 2012 Dec 1;125(Pt 23):5591-6.
Quail D, Joyce J. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine, 2013 Dec 1;19(11), 1423–1437.
Wang M, Zhao J et al. The role of the tumor microenvironment in tumorigenesis. Journal of Cancer 2017; 8(5):761-773.
Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer. 2015 Sep;15(9):563-72.
Moss Reports (purchase required): Excellent discussion of the hallmarks of cancer in general and how each complementary therapy affects the hallmarks. Select from the list of cancers down the left side of the page for a report describing uses of conventional, complementary, alternative and integrative therapies related to that cancer. Ralph Moss is among the most knowledgeable and balanced researchers of integrative cancer therapies. The cost of his Moss Reports is not negligible, but many patients find them of considerable value. Moss is also available for consultations.

Books

Alschuler LN, Gazella KA. The Definitive Guide to Thriving after Cancer. Berkeley, California: Ten Speed Press. 2013.
Lemole G, Mehta P, McKee D. After Cancer Care: The Definitive Self-Care Guide to Getting and Staying Well for Patients with Cancer. New York, New York: Rodale, Inc. 2015.
LeShan L. Cancer as a Turning Point, Revised Edition. New York, New York: Penguin Group. 1994.
Servan-Schreiber D. Anti-Cancer: A New Way of Life. New York: Penguin Group. 2008.

Professional Journals on the Tumor Microenvironment

Tumor and Microenvironment: a quarterly open access journal published by Wolters Kluwer|Medknow on behalf of the Primary Co-Development Institute of Medical Research, Beijing.
Cancer Microenvironment: Cancer Microenvironment is the official journal of the International Cancer Microenvironment Society (ICMS).
Journal of Translational Medicine: Cancer Microenvironment Section: The Cancer microenvironment section publishes research on the cellular and molecular components of the cancer microenvironment, with a particular focus on translational research that has important implications for the prevention, diagnosis and treatment of human neoplasms.

Video

The C-Word: neuroscientist David Servan-Schreiber discovered his own brain tumor during MRI research. He set out to gather as "much information as I could to see what I could do to help my body fight and resist cancer."

Websites

Dr. Hyman: 5 Strategies to Prevent and Treat Cancer
Jeannine Walston: Functional Medicine and Cancer
Personalized Lifestyle Medicine Institute: Cancer, the Tumor Microenvironment, and Personalized Lifestyle Medicine