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While the compounds most commonly associated with cannabis -- THC and CBD -- showed little to no effect, 10 other compounds were effective at inhibiting cancer cell growth. All Rights Reserved. Now, Penn State College of Medicine researchers say some cannabinoid compounds may actually inhibit the growth of colon cancer cells in the lab. The researchers tested the effects of synthetic cannabinoid compounds on colon cancer cells in an experiment in test tubes. While the compounds most commonly associated with cannabis — THC and CBD — showed little to no effect, 10 other compounds were effective at inhibiting cancer cell growth. Kent Vrana, chair of the Department of Pharmacology at Penn State College of Medicine, said the study — recently published in Cannabis and Cannabinoid Research — helped identify compounds that could be tested further to understand their anti-cancer properties. Colorectal cancer is one of the most common cancers diagnosed in the United States, according to the National Cancer Institute, with an estimated , newly diagnosed cases and 50, deaths in While medical cannabis has largely been used in recent years for palliative care, the researchers said some previous studies suggested that certain cannabinoid compounds may have the potential to inhibit or prevent the growth of tumors. To explore how effective cannabinoids were at reducing the viability of colon cancer cells specifically, the researchers tested how different synthetic cannabinoid compounds affected seven types of human colon cancer cells. The researchers incubated the cancer cells in a lab for eight hours before treating them with the cannabinoid compounds for 48 hours. Any compounds that showed signs of reducing the viability of one kind of cancer cell was then used to treat all seven kinds of cells. After further screening and analysis, the researchers identified 10 compounds that inhibited the growth of almost all seven types of colon cancer types tested. But while the researchers were able to identify these compounds, Vrana said they are still unsure about how exactly the compounds worked to reduce the viability of the cancer cells. Vrana said certain types of cells, like skin and colon cells, are more susceptible to cancers because they divide frequently. Vrana said that because the other compounds did not seem to be working through traditional cannabinoid signaling pathways, future research will focus on better understanding how the compounds interact with cancer cells and whether researchers can make the compounds more potent and effective. Wesley M. Yochum, associate professor of biochemistry molecular biology; and Daniel J. Morgan, assistant professor of anesthesiology and perioperative medicine, also participated in this work. Vesell Endowment helped support this research. Partnering with licensed private entities and collaborating with peer universities to tackle this priority of the Commonwealth supports the college's land-grant mission of research, teaching and service. The College of Medicine often investigates emerging therapies to advance the understanding of medical conditions, to formulate beneficial treatments, and to address unmet societal health needs. The college's research programs, including human clinical trials, are guided by ethical principles; conducted with honesty, integrity and accountability; and are in compliance with all applicable federal, state, and local laws and regulations. Research Cannabinoid compounds may inhibit growth of colon cancer cells. February 6, By Katie Bohn. Last Updated April 11, Katie Bohn kej psu. Get the news by email Subscribe.

Cannabis compound prevents colon cancer in mice

Colon buy Cannabis

Official websites use. Share sensitive information only on official, secure websites. Reviewed by: Jose A. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Colorectal cancer is a major public health problem. Unfortunately, currently, no effective curative option exists for this type of malignancy. The most promising cancer treatment nowadays is immunotherapy which is also called biological or targeted therapy. This type of therapy boosts the patient's immune system ability to fight the malignant tumor. However, cancer cells may become resistant to immunotherapy and escape immune surveillance by obtaining genetic alterations. Therefore, new treatment strategies are required. In the recent decade, several reports suggest the effectiveness of cannabinoids and Cannabis sativa extracts for inhibiting cancer proliferation in vitro and in vivo , including intestinal malignancies. Cannabinoids were shown to modulate the pathways involved in cell proliferation, angiogenesis, programmed cell death and metastasis. Because of that, they are proposed as adjunct therapy for many malignancies. By far less information exists on the potential of the use of cannabis in combination with immunotherapy. Here, we explore the possibility of the use of cannabinoids for modulation of immunotherapy of colon cancer and discuss possible advantages and limitations. Keywords: colorectal cancer, immunotherapy, cannabinoids, Cannabis sativa extracts, inflammation. Nowadays, colorectal cancer CRC is considered to be the third most deadly and the fourth most commonly detected cancer in the world 1. Despite the presence of highly advanced screening techniques, the incidence rate has been steadily increasing globally 2. Factors, like sedentary lifestyle, increased consumption of alcohol, tobacco, red meat, genetic predisposition, chronic inflammatory processes of the gastrointestinal tract, are triggering factors of this type of malignancy 4. Adenomatous polyps are known to be the main precursors of CRC. Understanding the pathogenesis of colorectal cancer is very important for choosing the right therapy. Etiology of CRC is complex and includes the accumulation of acquired epigenetic and genetic modifications that transform normal epithelial cells into malignant ones. The classical tumor progression model is called the development of the polyp- carcinoma sequence which involves three main steps. The first step is the formation of benign neoplasms like adenomas and sessile serrated polyps. The second step is characterized by the progression of benign tumors into more histologically advanced neoplasms, and the last step -their transformation into carcinoma. This process might take many years without showing any signs and symptoms. When CRC has developed, it still might take several years before it is diagnosed. CRC is caused by mutations in oncogenes, tumor suppressor genes, and genes involved in DNA repair mechanisms. Sporadic cancers arise due to point mutations, and the molecular pathogenesis of these cancers is very heterogeneous in nature. The inherited group of this particular malignancy is due to the inherited mutations and can be subdivided into two groups: polyposis and non-polyposis. The polyposis type includes mostly familial adenomatous polyposis which is characterized by the presence of numerous possibly malignant polyps in the colon. The non-polyposis variant is represented by Lynch syndrome 7. The familial CRC is also due to the inherited mutations, and it runs in the families without the presence of particular inherited syndromes 8. Recently, two molecular pathological classifications have been proposed based on the broad-range genomic and transcriptomic analysis of CRC. The hypermutated category is characterized by a high mutation rate, defective mismatch repair dMMR with a good prognosis, but poor prognosis after relapse. The ultramutated type has an extremely high mutation rate with DNA polymerase epsilon proofreading mutation and generally good prognosis. The poor survival rate after recurrence has been noticed in patients with this subtype. These classifications have provided information about a proper treatment selection and patients' prognosis, thus being very important for ongoing and future clinical trials. The main therapeutic options available nowadays for patients with CRC are surgery, chemotherapy, immunotherapy, radiotherapy. Due to subtle symptoms, more than half of patients are diagnosed when they have already developed advanced malignancies. Among new potential therapeutic approaches, treatment with cannabinoids and Cannabis sativa extracts have been shown to be efficient in inhibiting cancer growth in vitro and in vivo The main function of the endocannabinoid system is to maintain homeostasis The CB1 receptor is mainly expressed in CNS, and the CB2 receptor, being the most prevalent in the immune system, is mostly present in peripheral organs. In the past, tumors were defined as just a collection of homogeneous cancer cells. The aggressiveness of neoplasia has been described by its clinicopathological features. Recent progress in immunology and molecular biology has allowed us to become more familiar with the fundamental mechanisms of metastatic potential of tumors. Many studies in this field have broaden the knowledge and emphasized the importance of the immune system in the regulation of cancer growth. The main players of this process are innate immune cells like neutrophils, macrophages, mast cells, eosinophils, myeloid-derived suppressor cells MDSCs , and adaptive immune cells such as T and B lymphocytes 14 , Over the past decade, the knowledge of tumor microenvironment TME has become a key for understanding complex multistep tumorigenesis and developing novel treatment regimens and drugs The cancer microenvironment includes resident and non-resident cells that are interconnected by different mediators, and each of them have a specific function. The communication between these cells and tumor cells within their surroundings essentially regulates the destiny of tumor progression. Immune cells can either inhibit or favor tumor growth Table 1. New preclinical research has shown that non-antigen-presenting atypical cells are first targeted by the innate immune system; then, the inflammatory response promotes the formation of new blood vessels and the proliferation of tumor cells. Unfortunately, tumors can turn on the immunosuppressive mechanisms and escape the host immunosurveillance. Tumors might lose their antigenicity due to acquired faults in the antigen presentation, or they might be identified as self 25 — There are three phases of tumor immunoediting: elimination, equilibrium, and escape Figure 1. During the first stage, immune cells eliminate the neoplastic cells that express surface proteins. In the last phase, some cells can escape from being killed, and this subsequently leads to evasion and proliferation of resistant clones. In addition, the degradation of the extracellular matrix by matrix metalloproteinases and new blood vessels formed as a result of abnormal angiogenesis promotes the formation of metastases Phases of immunoediting in colorectal cancer. Elimination includes the removal of neoplastic cells, equilibrium describes the survival of a fraction of transformed cells, and escape describes the evasion and proliferation of these cells. As to the expression of cannabinoid receptors in the cells of the immune system, it has been demonstrated that the receptors are expressed in both adaptive and innate immunity. Therefore, it can be hypothesized that phytocannabinoids can influence the function of the immune system, regulate inflammation and possess antitumor effects, etc Inflammation plays a crucial role in colorectal carcinogenesis, and it is considered nowadays as one of the emerging hallmarks of cancer A better understanding of CRC and inflammation can lead to the development of new tumor biomarkers and more personalized and effective therapies. It is well-known that patients who suffer from chronic conditions such as inflammatory bowel disease have a much higher risk of developing CRC Inflammation is considered an important driving force of colitis-associated CRC cancers, while its role in sporadic and hereditary cancers is less clear. The evidence demonstrates that non-steroidal anti-inflammatory drugs may prevent or postpone the CRC development In general, inflammation plays a dual role in the neoplasia. Targeting malignant cells by cytotoxic T lymphocytes or diminishing the non-specific inflammation by T-regs can lead to an anti-tumorigenic response. This type of response is called protective and is associated with Th1 polarization and a lower recurrence of CRC. The cells of the innate and adaptive immunity and other cells such as fibroblasts, mesenchymal cells and pericytes are important in the cancer-associated inflammation The communication between these cells happens via a web of cytokines produced and secreted by immune cells after being stimulated. A higher level of IL is linked to a worse patients' survival, while studies on animals show that it has a protective role by suppressing inflammation 46 , IL-6 is an activator of the STAT-3 signaling pathway and is often found in CRC patients; and it is also linked to a worse survival and increased risk of relapse 37 , 57 , The stromal fibroblasts, obtained from colon cancer, produced prominent amounts of IL The last one induced tumor angiogenesis by enhancing VEGF production IL-6 facilitates the metastatic colonization of colorectal cancer cells. CRC cells can minimize the anti-tumorigenic effects of interferon signaling by the type I interferon receptor chain that leads to a poor response to anti-PD1 checkpoint inhibitors The increased expression of this cytokine strongly correlates with the more advanced tumors MACC1 induces cancer cell proliferation, survival and metastasis. The expession levels of this oncogene was reduced by knocking down the p65 NF-kB. Another study showed that the effect of peptide vaccine, AH1, on CT26 colon tumor-bearing mice caused a modest inhibition of tumor growth, but the combination with F8-TNF increased the anticancer activity drastically. The synergism between the peptide vaccine and TNF fusion protein was explained by F8-TNF causing rapid tumor hemorrhagic necrosis and as a result leaving small amount of residual cancer cells. IL-4 is actively released by colon cancer stem-like cells, and gives tumors a death-resistant phenotype. Neutralizing IL-4 with its antibody significantly sensitizes cancer cells to chemotherapy Early transgenesis of IL-5 in colitis-assosiated CRC mouse model increased the severity of colitis, induced the rate of polyps formation and as a result higher tumor load In patient was reported a case of extreme eosinophilia caused by IL-5 producing disseminated colon cancer Finding the best choice of treatment can be done by combining and analyzing information about the tumor-associated factors tumor localization, the presence of metastasis, the presence of biomarkers, etc. CRC patients with a metastatic disease receive a combination of chemotherapy and immunotherapy. Usually, the treatment lasts up to 6 months, but the duration significantly depends on individual cases The most common side effects of chemotherapy for CRC are leukopenia, polyneuropathy, diarrhea, thrombocytopenia, hyperemesis, hepato-renal dysfunctions, and the deterioration of the general condition. The severity of side effects is usually more profound in elderly patients and in patients with preexisting comorbidities Due to toxicity concerns, chemotherapy might not be suitable for many patients. Oncologists might not recommend this type of treatment due to some advanced stages of chronic diseases liver, kidney, and heart failures and a poor physical performance Immunotherapy is one of the most promising therapeutic modalities for patients with CRC Targeted therapy has revolutionized cancer treatment. Immunotherapy is a type of curative approach that helps the immune system to eradicate tumors. It can be classified into two main groups: active vaccines and passive monoclonal antibodies, adoptive cell therapy Table 3. Also, some biological therapies can particularly target certain designated tumor antigens, while others work non-specifically by enhancing the natural immune responses There are some types of cancer vaccines that have been studied in CRC treatment, such as a whole tumor -, peptide -, viral vector -, and dendritic cell DC vaccines. The aim of these agents like any other immunization strategy is to induce the antitumor immune response that will eradicate cancer and supply the organism with continuing surveillance to protect from its return. Some advantages of working with whole tumor vaccines are: they are easy to produce and are composed of all known and unknown tumor antigens. In contrast, the most significant disadvantage of these vaccines is a very low immunogenicity that can target normal cells and as a result, a low efficacy. Several approaches were made to augment the immunogenicity of whole tumor vaccines. The results suggest that the immunogenicity of these compounds has been improved Peptide vaccines are more specific for atumor-associated antigen, but the efficacy is still considerably low due to a small amount of T cell responses. The next type of vaccine is called viral vector vaccines. They are specific for a tumor-associated antigen and naturally immunogenic. The drawback of using them is their ability to cause a cytokine storm. The most used viruses in CRC are adenoviruses, poxviruses, and alphaviruses. Also, it suppressed the proliferation of colon adenocarcinoma in animal models. However, clinical trials done in patients with advanced stages of colorectal cancer demonstrated a lack of responses The dendritic cell vaccines are characterized by the tumor-associated antigen specificity and generation of an organism's own immune response. The negative aspects are high costs and a very time-consuming preparation process. After the complete excision of CRC liver metastasis, the phase II vaccine clinical trial showed fewer and delayed relapses in the vaccine arm in comparison with the observation arm Results of DCs vaccines are very encouraging, and soon their efficacy can be significantly improved. Adoptive cell transfer therapy is another type of immunotherapy. The main advantages of this cure type are the elimination of the need to produce the immune response and high tumor specificity. In contrast, some disadvantages are high costs, long preparation time, and target-dependent toxicities. In this therapy, the autologous T cells are withdrawn from the tumor, lymph nodes or peripheral blood of a patient and modified ex vivo by making them expand and adding some co-stimulatory molecules and cytokines. Then a passive transfer of these T cells into the host is done for the direct tumor destruction. The most recent discovery of this type of passive immunotherapy is the development of engineered T cells that express the chimeric antigen receptors specifically for carcinoembryonic antigen A phase I trial performed in patients with CRC resistant to the standard treatment protocol regimen by using the autologous T cells modified to express a murine CEA T cell receptor showed a significant decrease in serum CEA in all three patients; in one of them a clinical response by the presence of metastasis regression in the liver and lungs was demonstrated. At the same time, these patients experienced transient inflammatory colitis Two weeks after laparoscopy, a drastic increase in CEA levels was observed. Adoptive cell transfer allowed to decrease the serum level of CEA, eventually bringing it to normal. A noticeable size reduction of the unresectable liver metastasis was observed. During the follow-up examination in 19 months, no progression or relapse was noted, and the levels of CEA remained within normal limits Highly specific monoclonal antibodies have been very effective in cancer treatment for decades. Bevacizumab, a humanized monoclonal antibody against VEGF, suppress the tumor growth and angiogenesis as well as modulates the immune system of a host by increasing the population of B and T cells The dramatic efficacy of antibody-based immunotherapy was proven with the use of another type of monoclonal antibodies mAbs known as checkpoint inhibitors ICIs. The latter one is expressed in the naive T-cells, effector T-cells, and regulatory T-cells T-regs. It stimulates the deactivation of T-regs via binding to the antigen-presenting cells. Together with its ligand, this receptor causes the exhaustion of T-cells by minimizing the tumor-infiltrating lymphocytes and T-cell proliferation. Consequently, tumors acquire immunoresistance. The latter one has a less effective response to ICIs and a worse prognosis The most common side effects related to the therapy were pruritus, rash, diarrhea and fatigue. The approval was granted in July , after the report of the results of the phase II CheckMate trial During the follow-up at Thirteen percent of patients were obliged to stop treatment because of the drug-related side effects. This combination demonstrated the superior efficacy than anti-PD-1 monotherapy. There is a need to find drugs that will target an immune response and will also promote the T-cell infiltration. Due to a low mutational and neoantigen load, it is difficult to reach these aims. Current regimens include radiotherapy, chemotherapy, and anti-angiogenic substances for enhancing the immune activation, the killing of tumor cells, and the elevation of tumor antigens. Later on, the treatment may be combined with ICIs and other biologics. There are currently some ongoing clinical trials that evaluate the effects of chemotherapy with either anti-PD-1, anti-PD-L1 ans external beam radiation therapies or radiofrequency ablation Another approach that has been well-studied is a combination of the mitogen-activated protein kinase inhibitors MEK like Cobimetinib and Atezolizumab. No advanced therapy-related adverse effects were noted. Later on, 84 patients were included, and results were updated. ECS actively regulates gut homeostasis. All components of ECS are highly expressed in the intestinal tissue, meaning that this system directly affect the proper functioning of gastro-intestinal system. CB1 and CB2 receptors are expressed in healthy colon epithelium, submucosal myenteric plexus, and smooth muscles, plasma cells in the lamina propria; CB2 receptor is also present on the intestinal macrophages 88 , TRPV1 receptor is expressed on colonic nerve fibers The GPR55 receptor is present in the mucosa and the muscle layer of the colon The main degradation enzymes of endocannabinoids, FAAH and MAGL enzymes are distributed on colonic epithelium glands, lamina propria, and myenteric plexus. To understand the role of ECS in the gut, it is important to distinguish the effects of increased and decreased cannabinoid tone in the gastro-intestinal system. In general, CB1 receptor antagonists reduce the cannabinoid tone in the gut and lead to vomiting, diarrhea, increased gastric emptying, and gastro-intestinal transit. In contrast, CB1 and CB2 receptor agonists, as well as MAGL inhibitors and FAAH blockers lead to an increase in intestinal cannabinoid tone by reducing vomiting, gastric acid secretion, and gastric emptying, as well as reducing hypermotility, diarrhea, and visceral pain In contrast, silencing of the CB2 receptor did not show any effect on polyp growth The CB2 receptor expression is increased in CRC and is considered as a poor prognostic factor for this type of cancer ECS is a very important factor of CRC pathogenesis, suggesting a potential impact of cannabinoids in this disease. The medicinal plant that has recently gained a lot of attention in the cancer field is Cannabis sativa. Many in vitro and in vivo experiments have shown that cannabinoids and cannabis extracts inhibit proliferation, stimulate apoptosis and autophagy, suppress angiogenesis and metastasis 98 — It was found that the inhibitory effect of CBG on colorectal cancer cells viability was time dependent. The induction of apoptosis was shown by an increase in the activity of caspases 3 and 7, the presence of DNA fragments, an increase in the expression of CHOP. CBD was also demonstrated to have the antiproliferative effects in colorectal cancer models. This effect was due to the activation of caspase-3 and a decrease in the phosphorylated form of Akt-protein When the levels of Noxa were suppressed by siRNA, the expression of apoptosis markers became significantly reduced. Similarly, after the blockage of ROS production, the level of Noxa were reduced. The effects of full botanical extracts, such as high CBD botanical drug substance BDS , on colon cancer were also studied. Such extracts are typically prepared from cannabis flowers that are rich in CBD, or CBD isolate is added spiked to a certain concentration. It was hypothesized that other components of cannabis plant extracts may act synergistically with CBD and can be useful from a therapeutic point of view. In vivo studies showed that using chemically induced carcinogenesis by AOM, C. In xenograft models, CBD BDS significantly reduced the tumor volume, but no difference in the growth of tumors was observed after 1 week of treatment The anti-cancer potential of cannabinoids in CRC is summarized in Table 4. Slow development and approval of new anti-neoplastic drugs for CRC is due to the lack of proper preclinical models. However, due to mentioned differences, correlation between these models is not very strong Clinical trials, on the other hand, are golden standard for testing and approval of any potential drug. It is important to mention one clinical study that has investigated the largest number of cancer patients receiving medical cannabis between and in Israel. Two thousand nine hundred seventy patients suffering from the breast Interestingly, most patients received more than one strain. Nine hundred two Out of the remaining patients, Before initiating the treatment, only Among the all cancer-associated symptoms, nausea, vomiting, depression, migraine, and sleep disorders, were the most improved. The most common side effects of cannabis treatment at 6 months of follow up were dizziness, xerostomia, and increased appetite. The psychoactive adverse effects were noticed by 2. It was concluded, that medical cannabis is a well-tolerated and safe palliative therapeutic option for cancer patients Being immunomodulatory agents, cannabis extracts and single cannabinoids can affect both the innate and adaptive immune responses. Generally, cannabinoids are considered as immunosuppressive compounds. They influence the innate immune responses by suppressing the activity of NK cells, dendritic cells, the migration of neutrophils and macrophages with their antigen presentation and phagocytosis processes , and by triggering the induction of MDSCs , Inflammation is the main mechanism of the innate immune responses. In general, cannabinoids, such as THC and CBD, cause the downregulation of pro-inflammatory cytokines and the upregulation of anti-inflammatory cytokines. By doing this, they actively suppress the inflammation process However, some studies demonstrate that these compounds have different effects on inflammation by either enhancing or suppressing it. These contradicting results might be tissue- and dose-specific. Cannabinoids may affect the adaptive immune responses by influencing the humoral and cellular immunity. The T cell immunity can be influenced by cannabinoids in different ways: they can affect the proliferation and the number of T cells by polarizing the cytokine response to either Th1 or Th2 Cannabinoids have been shown to suppress the proliferation of T cells, to cause their apoptosis and support the Th2 polarization , Some of the initial in vitro and in vivo studies of THC showed an immunosuppressive effect on the T cells and B cells when high concentrations were used, while the immunostimulatory effects was observed at low concentrations The experimental research conducted in vivo with SIV-infected macaques that were receiving THC for the period of 17 months demonstrated an increase in T cells, the reduction in viral load and an increase in the expression of Th2 cytokines THC-negative counterparts Concerning the role of CBD, it was also shown that it could act as an immunosuppressant of Th2 in vitro and in vivo by polarizing the cytokine response to Th2 and working as an immunostimulant to Th1 Concerning the humoral immunity, some reports from human studies showed the reduced number of B lymphocytes and the decreased amount of IgM and IgG after cannabinoid ingestion in the form of bhang The immunomodulatory effects of cannabis are well-documented. Nowadays, there are many well-known cannabis cultivars, and each one has a unique composition of different compounds. Many studies have demonstrated the effects of single cannabinoids, such as THC and CBD, on inflammation and cancer cell growth Other components of the plant such as minor cannabinoids, terpenes, terpenoids, flavonoids, and others may act synergistically with cannabinoids and can be useful from a therapeutic point of view. Like with any other drug, the effects significantly depend on the concentration. In the future, with more research being done, we might gain more insight into the potential immunostimulatory effect of individual cannabinoids or cannabis extracts. This knowledge can help medical professionals to integrate cannabis extracts into cancer targeted therapy, potentially as adjunct therapy. The special extracts with strong anti-neoplastic activities should be identified that are not cytotoxic to normal cells and can sensitize cancer cells to further treatment without reducing the immune responses. Then, these extracts can be combined with immunotherapy, and such combination may have a synergistic action. The results of the retrospective analysis performed with patients with melanoma, renal carcinoma and non-small cell lung cancer when cannabis was used in combination with an immunotherapeutic agent Nivolumab showed a decrease in RR but no changes in PFS and OS. More studies are needed to investigate the possible interactions between cannabinoids and immunotherapy drugs A thorough exploration of cannabis research and associated drugs should be performed. Currently, we have limited data about cannabis interactions with other drugs, especially with targeted therapy. Since the immune checkpoint inhibitors are a type of the most successful and effective immunotherapy for CRC patients. Therefore, research on the possibility of enhancing the immunotherapy by cannabis extracts should be conducted Figures 2 , 3. The potential of cannabinoids for cancer immunotherapy. The upper panel shows how cannabinoids can increase tumor immunogenicity. The release of tumor antigens might be increased due to the direct cytotoxicity of cannabinoids in cancer cells. Next, the presentation of enhanced tumor antigens occurs followed by an increase in T cells-mediated immune response and T cells lysis of tumor cells. The lower panel shows how cannabinoids can reverse tumor immunosuppression. Macrophages can be reprogrammed into an antitumor phenotype with the help of cannabinoids. M1 immunostimulatory macrophages secrete the anti-tumorigenic cytokines and effectively phagocytize cancer cells. The first approach could be focused on finding extracts that can increase tumor immunogenicity. Because of that, tumor cells will be more susceptible for the immune system recognition. In such case, in vivo research would be beneficial to study cannabis as a neoadjuvant therapy before starting biologics. This should be followed by studies testing whether there is an enhancement in the adaptive immune responses mediated by T cells. By directing cytotoxicity to cancer cells, cannabis extracts might increase the release of tumor antigens followed by the enhanced antigen presentation. Also, changes in the tumor microenvironment such as the MDSC and Treg infiltration should be evaluated. The second approach could focus on the possibility of reversing the tumor-induced immunosuppression by using extracts. For example, this can be done by reprogramming macrophages into the antitumor phenotype. Being highly plastic cells, macrophages can easily switch from a pro-tumorigenic to an anti-tumorigenic type. By finding extracts that can influence this particular pathway, one can combine them with immunotherapy to show a synergistic action. In addition, the assessment of macrophage polarization can be done by studying cytokines. Cannabis extracts that polarize macrophages to the M1 type and do not possess the anti-inflammatory properties can further be combined with immunotherapy. It has been strongly suggested in the literature that cannabinoids and cannabis extracts can be used for the treatment of colorectal cancer. Evidence shows that cannabinoids have a high potential to be turned into promising drugs. It is obvious that these compounds can target the key signaling pathways of cancer development. In addition, more preclinical and clinical assessments of cannabinoids as anti-CRC and immunomodulatory agents should be done. An additional research would help us find new preventive and therapeutic opportunities for patients that are at risk of developing CRC or are currently struggling with it. By introducing these potent compounds into the current treatment protocols, one can achieve a dose reduction of other drugs that are highly toxic, thus reducing undesirable side effects; similarly, cannabinoids may likely sensitize malignant cells for further targeted therapy. Moreover, further studies of tumors, especially their sequencing, will provide more information about their specific characteristics. The knowledge about how the genetic pathways interact with certain cannabinoids can help doctors prescribing them according to the cancer's genetic makeup. Due to that, medical personnel will prescribe cannabinoid-based therapies to a particular patient with a specific malignancy. The treatment will become patient-oriented and indication-specific. As a consequence, cancer prognosis and its survival rate might significantly improve. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. As a library, NLM provides access to scientific literature. Front Med Lausanne. Find articles by Mariia Zaiachuk. Find articles by Nazar Pryimak. Find articles by Olga Kovalchuk. Find articles by Igor Kovalchuk. This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine. Received May 21; Accepted Aug 24; Collection date Open in a new tab. Increases levels of IL-6 and IL Linked to a worse survival, increased risk of relapse. Induction of tumor angiogenesis by enhancing VEGF production. Inhibition of colon cancer cells motility and invasion. Anti-tumorigenic effect by slowing cancer progression. Causing chemoresistance. Exacerbate the disease severity. Promotes the survival, invasion and metastasis of CRC cells. Reduces response to immune checkpoint inhibitors. Promotes apoptosis of cancer cells, inhibits angiogenesis and tumor growth. Immunotherapy Advantages and disadvantages Status of approval in CRC References Whole tumor vaccines Composed of all known and unknown tumor antigens, easy production Not approved 66 Low immunogenicity and efficacy Peptide vaccines The known specificity for the tumor-associated antigen Not approved 67 66 Low efficacy Viral vector vaccines Specific for the tumor-associated antigen, naturally immunogenic Not approved 68 66 Cytokine storm induction Dendritic cell vaccines Tumor-associated antigen specificity, the generation of the own immune response Not approved 69 High cost and time-consuming preparation Adoptive cell therapy High tumor specificity, the elimination of the need to produce an immune response Not approved 70 71 High cost, long preparation time, target-dependent toxicities Antibody-based immunotherapy Target immunosuppressive pathways, the enhancement of the anti-tumor immune response Bevacizumab Cetuximab Panitumumab Ipilimumab Nivolumab Pembrolizumab 72 73 74 Toxicity. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Release cytotoxic cytokines Antigen presentation to T cells. Direct lysis of cancer cells Release cytotoxic cytokines. Suppress anticancer immune responses Enhancement of pro-inflammatory cytokine production. Promote angiogenesis, tumor proliferation, chemotaxis, invasiveness, and metastasis. Release immunosuppressive molecular mediators Suppress T cell functions Recruit immunosuppressive immune cells. Release cytotoxic cytokines Directly kill cancer cells. Granzyme A expressed on NK cells promotes cancer development by enhancing inflammation. Inhibit cancer cell growth, increase in inflammatory anti-tumor reaction. Promote cancer growth by stimulation of neoangiogenesis, tissue remodeling and by modulation of the host immune response. Macrophages, T lymphocytes, NK cells, mast cells, eosinophils. Inflammation stimulation, resistance to infection and cancers. Stimulation of cellular differentiation, inflammation and the development of effector T cells; induces synthesis of acute phase proteins. A signal transducer and activator of transcription STAT5 , influences the differentiation of T helper cells, activates cytotoxic lymphocytes. Monocytes, lymphocytes, mast cells, macrophages, T helper cells Th2 , regulatory T cells. Limiting a host immune response to pathogens, tissue homeostasis maintenance, the prevention of autoimmune conditions development; decreases antigen presentation and phagocytosis, enhances T reg cells. Dual role: suppressing inflammation, linked to a worse patients' survival. Gives tumors a death-resistant phenotype. Stimulates the proliferation of B cells and their differentiation to Ig-secreting cells. Controls cell proliferation, differentiation, wound healing; inhibition of B cells and activates macrophages; promotes T cells differentiation. Chemokinesis and migration induction of T cells, anti-viral activity. Composed of all known and unknown tumor antigens, easy production. The known specificity for the tumor-associated antigen. Specific for the tumor-associated antigen, naturally immunogenic. Tumor-associated antigen specificity, the generation of the own immune response. High tumor specificity, the elimination of the need to produce an immune response. High cost, long preparation time, target-dependent toxicities. Target immunosuppressive pathways, the enhancement of the anti-tumor immune response. Anti-angiogenic, antimetastatic; VEGF inhibition.

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