Cannabis & the Tumor Microenvironment
by Daniel Gana, MSc & Abraham Benavides, MD
Cancer cells are rebels, breaking the rules that keep our bodies in balance. These rogue cells rely on a sophisticated communication and supply chain network powered by a tumor microenvironment to thrive.
Picture the tumor microenvironment as a bustling military base built to serve cancer’s needs. It comprises misguided immune cells, blood vessels supplying nutrients, connective tissue, and signaling molecules for communication. These components help cancer cells grow, evade detection, and resist treatments.
Communication is one of cancer’s most powerful tools for survival and growth. By exchanging signals, cells coordinate actions like multiplying, invading nearby areas, and avoiding detection by the immune system. This teamwork also helps them get support, like nutrients or protection.
One fascinating aspect of this communication channel is the endocannabinoid system’s role (ECS). While the ECS is best known for regulating mood, appetite, and pain, cancer cells appear to hijack this system for survival. Cannabinoid receptors, like CB1 and CB2, a part of the ECS, are identifiable on the
surface of cancer cells and can be targeted by cannabis constituents like cannabinoids, terpenes, and flavonoids.
THE ROLE OF THE ECS IN A TUMOR MICROENVIRONMENT
Cannabinoid receptors on the surface of cancer cells serve as messengers, sending and receiving signals that control activities in the tumor microenvironment. Once the cell is corrupted, these receptors control tumor growth, enable cancer cells to spread, and even suppress the immune system’s ability to fight back.
Some of the roles of the hijacked ECS in the tumor microenvironment are highlighted below:
Signals transmitted through CB1 and CB2 receptors can play a complex role in cellular processes, including tumor growth. When hijacked by cancer cells, these receptors enhance tumor progression by promoting cellular proliferation and survival. This occurs as signaling through CB1 and CB2 influences pathways such as PI3K/Akt and ERK/MAPK, which are crucial communication pathways in the human body for cell growth and the inhibition of programmed cell death (apoptosis).
By reducing apoptosis and expressing themselves in disguise as part of us, these receptors allow abnormal cells to evade the natural mechanisms that would typically eliminate them, contributing to tumor development. Additionally, receptor activation can alter the tumor microenvironment by promoting the formation of new blood vessels (angiogenesis) and suppressing immune responses, supporting tumor survival and expansion.
The hijacked ECS plays a crucial role in helping cancer cells evade detection by the immune system through its ability to manipulate immune cell function. By activating CB1 and CB2 receptors on immune cells (such as macrophages, T cells, and natural killer cells), the ECS can suppress immune responses that would otherwise target and destroy cancer cells.
One mechanism involves the ECS creating an immunosuppressive tumor microenvironment. This shift weakens the ability of immune cells to recognize and attack malignant (cancerous) cells. Additionally, ECS activation can downregulate the expression of major histocompatibility complex (MHC) molecules on cancer cells, further masking them from immune detection.
The ECS may also promote the recruitment of regulatory T cells (Tregs), suppressing antitumor immune activity.
The endocannabinoid system influences the ability of cancer cells to spread to other parts of the body, facilitating metastasis. By manipulating CB1 and CB2 receptors, the ECS regulates several key processes involved in metastasis, including cell migration, invasion, and adhesion.
Inappropriate activation of these receptors can enhance the expression of proteins that promote cell movement, such as matrix metalloproteinases (MMPs), which break down the extracellular matrix, allowing cancer cells to invade surrounding tissues and blood vessels.
The ECS can also influence the tumor microenvironment by recruiting inflammatory cells that secrete cytokines (small proteins that act as messengers in the immune system) and growth factors, further aiding cancer cell invasion and creating favorable conditions for metastatic spread.
HOW CANNABIS DISABLES CANCER COMMUNICATION & GROWTH
While the ECS can be hijacked by cancer for its nefarious purposes, introducing whole plant-based cannabis compounds can help restore the lost ECS controls and diminish cancer’s driving forces.
Cancer cells depend on constant communication to grow and survive. They exchange messages with nearby cells, such as immune cells, support cells, and blood vessel cells, to create a favorable environment. These signals help cancer evade the immune system and even build new blood vessels, which supply the tumor with nutrients to thrive. This communication enables cancer cells to evade the immune system, build new blood vessels for nutrients, and resist therapeutic interventions.
Phytocannabinoids like CBD, CBGA, and CBDA interact with the endocannabinoid system (ECS), among dozens of other non-ECS targets (e.g., TRP receptors, etc.), to disrupt these critical signaling pathways. When these pathways are disrupted, cancer cells lose their ability to maintain the supportive environment they need.
By cutting off these vital lifelines, the plant-activated ECS weakens cancer’s defenses and makes it more vulnerable. For example, CBD has shown promise in targeting cancer cells by reducing inflammation and limiting the formation of new blood vessels. These blood vessels are essential for supplying tumors with nutrients, cutting off cancer cells’ food supply.
CBDA works by inhibiting messaging enzymes like COX-2, which are linked to cancer spread (metastasis). By suppressing inflammatory signals that promote cancer spread, CBDA helps limit the tumor’s ability to invade new tissues, helping to keep cancer growth under control.
CBGA disrupts the metabolic processes cancer cells rely on for energy, explicitly targeting pathways like glycolysis. This cuts off the tumor’s energy supply and slows its growth and progression, thereby weakening its ability to survive.
THC and its aged derivative CBN promote apoptosis, or programmed cell death, in cancer cells. This disrupts their communication networks and limits their survival, creating a less favorable environment for tumors to grow.
When compounds from the ECS bind to receptors on cancer cells, they help reduce inflammation, creating an environment that works against tumor progression. Inflammation often fuels cancer growth and spread, so targeting this process weakens the tumor’s ability to thrive.
The ECS also influences how immune cells operate within the tumor micro-
environment. For example, it can reduce inflammatory immune cells and enhance the function of those targeting cancer cells.
Cannabis-based medicine holds significant potential for the future of cancer therapy, mainly through the use of whole-plant, full-spectrum extracts. These extracts contain many cannabinoids, terpenes, and flavonoids that work synergistically to activate the endocannabinoid system (ECS).
By ensuring the ECS is functioning optimally, full-spectrum cannabis extracts could play a key role in promoting overall health and potentially reversing the abnormal actions of cancer cells and their ECS takeover. Restoring the lost ECS control and balance may help cancer patients in many tangible ways.
Targeting the ECS also offers advantages in reducing side effects commonly associated with cancer and conventional cancer therapies like chemotherapy and radiation. Cannabis-based treatments can help mitigate pain, reduce inflammation, and improve appetite without causing the severe toxicities seen in many traditional treatments.
GLOSSARY
ANGIOGENESIS is when new blood vessels form from existing ones in both healthy and diseased states
APOPTOSIS is natural (programmed) cell death
CANNABINOIDS (CBD, CBGA, CBDA) are a few of the cannabis plant’s chemical compounds that act as ligands (signaling messengers) in human biological processes
CANNABINOID RECEPTORS (CB1, CB2) are protein receptors distrib-
uted throughout the human body that receive the messaging signals from ligands that turn biological systems on/off (see cannabinoids above), concentrated in the brain and central nervous system (CB1) and immune system (CB2)
CYTOKINES are proteins that regulate the immune system and control inflammation
ENDOCANNABINOID SYSTEM (ECS) is the master regulatory system that creates endogenous (human-made) cannabinoids that control essential bodily functions (sleep, pain, appetite, emotions, learning, memory, etc.)
ENZYMES are proteins with a specific attraction to unique molecules that speed up chemical reactions (like growth, blood clotting, and digestion)
FLAVONOIDS plant pigments that act as antioxidants in the human diet (protecting cells from free radicals, which may play an active part in the growth of cancer, heart, stroke, and other age-related diseases)
GLYCOLYSIS is the process of sugar (glucose) being turned into energy for a cell, occurring in the cytoplasm (jelly-filling), where most chemical reactions occur, and protein is made
MACROPHAGES are white blood cells in the immune system that clear out waste and stimulate immune cell activity
MATRIX METALLOPROTEINASES (MMPs) are enzymes that break down proteins between cells, enabling tissue remodeling (like blood vessel growth and wound healing) to occur
METASTASIS is the growth (spread) of cancer at a secondary site
PROLIFERATION is the rapid reproduction of cells
T CELLS (Tregs) are white blood cells that grow from stem cells in bone marrow, playing a key role in the immune system’s ability to respond adaptively to viruses, foreign cells, and cancer cells they encounter
TERPENES are plant lipids that provide the unique aromas and flavors of botanicals, cannabis, and food and act as building blocks for the production of enzymes and other vital compounds used in biological pathways
