Layperson Version
Immunology's Cruelest Enemy & Greatest Challenge
You have probably seen this popular sign by now with a red slash through the word "Cancer":
You’ve just gotta love it. I doubt there are many words in the human vocabulary that engender more anxiety, uneasiness, and fear than the word “cancer.” It’s so near and painful to almost all of us with either an unfortunate direct, personal experience with the disease or agonizing over a loved one, family member, or friend suffering through a cancer diagnosis. So, kudos to MD Anderson (or whoever created their signage) for “crossing it out” as is everyone’s hope. Thank you.
To understand cancer, one must not think of it as a noun, but rather as a verb. The rate of acquired mutations in the human genome with about 37 trillion cells in our bodies is in the trillions.” Only an infinitesimal amount of them (less than 60 per gene), override the suppression of these mutations, called “apoptosis,” to produce genetic disorders and disease.” Nonetheless, those mutations are continually occurring, and virtually all mutations have the potential to become irregular, accumulate, or mutate into cancer. Thus, if you
TABLE 6.1
follow the mathematical law of large numbers, it follows that “If you live long enough, or your luck runs out earlier, you will get cancer.” Thus, throughout our lives, we are all “cancering."
There are over 185 types of cancers, according to the National Cancer Institute (Table 6.1), and leading the list of the top 10 cancers in America (Table 6.2) is skin cancer, followed by lung cancer which is the leading cause of cancer deaths and the second leading cause of all deaths in America. According to the Centers for Disease Control, cancers are the second leading cause of death in America, second only to cardiovascular deaths. Tragically, in 2020 COVID-19 became the leading cause of death in the U.S. just behind heart disease and cancer.
Indeed, with cancer, we are dealing with a devastating disease that is being better understood with an expanding commitment to immunologic, genetic, and cancer research. A 26-year decline in cancer mortality is driven primarily by a long-term decrease in death rates for the four major cancers; lung, colorectal, breast, and prostate. The drops we are seeing are likely due, at least in part, to the improved diagnosis and management of the common cancer types as well as more public health education and messaging about cancer prevention (e.g., smoking cessation advertising). Also, immunotherapy has had a profound effect on our ability to better treat and control cancers.
Sadly, data since 2020 has indicated a resurgence in the rates of cancer development and mortality by as much as 26%. Contributing to and exacerbating this distressing trend are the direct and indirect effects of COVID-19 over the past 3 years. The virus has been identified as a significant risk factor in multiple ways. The immunocompromised and immunosuppressed cancer patient becomes more vulnerable to SARS-CoV-2 infection and a resultant increased mortality risk. Epidemiologically, the pandemic has decreased access and caused delays in early cancer diagnosis and care due to the increased inaccessibility of hospital and medical care secondary to the overburdened healthcare system from COVID-19 patients.
Blog #28: Cancer: Immunology’s cruelest enemy and greatest challenge (Part 2: What is it, really?)
Inherited genetic disorders result in gene alterations in virtually every cell in our body. As a result, these disorders tend to affect many tissues, organs, and body systems. When genetic screening identifies an inherent risk in one’s genome, for example a known cancer gene such as BRCA1, BRCA2, or PALB2 gene for breast cancer, management may include counseling, more frequent cancer screening, or even preventive (prophylactic) surgery to remove the tissues at highest risk of becoming cancerous (e.g., preventive mastectomy). In our immunology and genetics discussions, we have discussed environmental factors (carcinogens) and radiation-caused mutations that may contribute to the development of cancer. The damage to our DNA through both injury and chronic irritation (remember our previous comments on smoking in Blog #18?) all can lead to cumulative mutations and resultant “cancering.” But up to now, we haven’t considered the possibility of a random mistake (called oncogenesis) in one of those trillions of normal DNA replications that aren’t suppressed and result in a cancer-causing mutation. A series of these mutations (carcinogenesis) in a specific gene class can transform a normal cell into a neoplastic, cancer cell.
Beyond “a random genetic mistake” causing cancer, there are several other genetic irregularities that can create carcinogenesis. Epigenetics (see Blog #10) is the study of changes in organisms (humans included) caused by modification of gene expression or their protein production rather than alteration of the genetic code itself. As with all genetic activity, epigenetics can turn gene expression on or off by the DNA genetic code or by environmental factors. Such abnormalities can produce unpredictable cancers.
Proto-oncogenes are genes that promote cell growth and cellular division, whereas tumor suppressor genes discourage cell growth, or briefly halt the process of DNA repair. A series of many mutations to these proto-oncogenes are needed before a standard cell transforms into a neoplastic cell. This phenomenon is referred to as “oncoevolution.” Tumor suppressor genes that are activated by cellular stress or injury that produce free-floating genetic material can trigger enzymes and pathways that result in the activation of a tumor suppressor gene, p53. This tumor suppression protein arrests the progression of the abnormal cell cycle and prevent mutations from being passed on to subsequent cells. This p53 protein has been named the “guardian of the genome.”
It is estimated that about 20% of cancers are caused by infectious agents. Organisms of the microbiome and its dysbiosis or an imbalance between the types of organisms it includes, can induce carcinogenesis through direct DNA damage and inflammation, indirectly through modulation of immune responses, or by chronic inflammatory responses induced by bacterial metabolites (back to the “danger hypothesis). Among infectious agents, viruses tend to have a higher risk as carcinogens, although bacteria and parasites may also be implicated. Some viruses can disrupt signaling that normally keeps cell growth and proliferation in check. Also, infections can weaken the immune system or cause chronic inflammation that may lead to mutations and subsequent cancers. The most significant viral risks for cancers include the following:
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Epstein-Barr Virus (EBV): Risk of lymphoma and cancers of the nose and throat;
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Hepatitis B Virus and Hepatitis C Virus (HBV and HCV): Risk of liver cancer;
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Human Immunodeficiency Virus (HIV): Risk of Kaposi sarcoma, lymphomas (including both non-Hodgkin’s lymphoma and Hodgkin’s disease), and cancers of the cervix, anus, lung, liver, and throat;
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Human Papillomaviruses (HPVs): Risk of all cervical cancers and penile cancers;
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Human T-Cell Leukemia/Lymphoma Virus Type 1 (HTLV-1): Risk of adult T-cell leukemia/lymphoma ATLL);
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Merkel Cell Polyomavirus (MCPyV): Risk of Merkel cell carcinoma;
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Helicobacter pylori (H. pylori): Risk of stomach cancer.
Blog #29: Cancer: Immunology’s cruelest enemy and greatest challenge (Part 3: Microbiome, XCI and microRNA): We are beginning to find out
As mentioned in our discussion of infectious agents (in our last Blog #28), it is estimated that individual microbial pathogens contribute to cancer development in approximately 20% of total cases. Among these pathogens, genetic mutations are the main drivers of tumor initiation, with contributions from secondary risk factors like diet, age, lifestyle factors, microbes, etc. However, we now know that the microbiome can regulate the effects of tumor-driven mutations and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. The microbiota may affect tumor immunity by regulating the host immune system and the tumor’s microenvironment.
Some bacteria help fight tumors by activating immunity, while others induce immunosuppression to help cancer cells escape from the immune system. The composition of the intestinal microbiota that is sensitive to treatment or prone to adverse reactions can be used as biomarkers to predict the prognosis of immunotherapy and may also assist the immunotherapies. The role of the microbiota in regulating not only gut but also systemic immune responses is being studied as to the impact on cancer immunotherapies, particularly with agents targeting the immunologic checkpoint inhibitors we discussed previously under monoclonal antibodies, checkpoint inhibitors in Blog #21. We’ll mention a few below under “sex-specific clusters” and then later under “combination strategies” in Blog #34.
Efforts are underway to establish the role of each microbe or group of microbes in different kinds of cancers. Physiological responses to immunotherapy, antibiotics, radiation, and chemotherapy in microbes need to be explored. There are numerous immunotherapy strategies being implemented to manipulate multiple immune pathways and molecules. These strategies and increased understanding of the gut microbiomes in immunotherapy has provided a significant impact on clinical therapeutic drugs. The immunologic status of the host, tumor invasion status, and biology of malignancies are determining factors for individualized therapy. Additional research on the microbiome will undoubtedly lead to the earlier treatment of various cancers.
MicroRNAs (miRNA) are small noncoding RNA molecules, the kind not involved in protein synthesis, we discussed back in Blog #13, possess enormous regulatory powers. They play key roles in almost all physiological pathways, and more so for our discussion, in the causes of autoimmune diseases and cancers. Their genomic distribution as previously described in Blog #12 mentions their highest density of sequences on the X chromosome. It is estimated that miRNA regulates up to 50% of all protein-coding genes. Based on “lyonization” or XCI (X chromosome inactivation) described back in Blog #12, this prodigious, complex embryologic (and evolutionary) genomic process equips females with greater miRNA machinery than males - “for better and for worse” (pardon the pun).
In previous blogs, we have already demonstrated some of the multiple ways that molecular biology contributes to the female predilection for autoimmune diseases as well as cancer risks for both males and females. Now let’s consider some additional examples to accentuate the profound influences (and paradoxes) the miRNA and X chromosome amalgam produce. The female immune system is flexible in its ability to counteract infections and noninfectious diseases, including cancers. This advantage, however, is yet again another paradox of the immune system in that it can result in increased susceptibility to developing autoimmune diseases. Meanwhile, a significant number of X-linked miRNAs help in regulating the immune system, but also have oncogenic potential. To add to this complex puzzle, there exist miRNA-dependent, sex-specific clusters that can both regulate immune responses and provide T-cell cancer immunosurveillance against tumors. Relative to breast cancers, the most common cancer in women, the 2 circulating X-linked miRNAs have been identified as promising diagnostic biomarkers. Continued research will lead to the identification of new biomarkers for additional forms of cancer.
Blog #30: Cancer: Immunology’s cruelest enemy and greatest challenge (Part 4: Getting a handle on it early)
The disease path for cancers is the abnormal growth of cells different in type, numbers, and actions of otherwise normal cells for the tissue or organ system in question. The growth of cells can be rapid or slow. Cell accumulation can be minuscule or massive. The ultimate clinical criteria for a cancer diagnosis are that the cells in question are distinctly different, microscopically and macroscopic, from the ordinary cell evolution, appearance, and growth.
As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed, forming growths called tumors. Many cancers form solid tumors, whereas cancers of the blood, such as leukemias, generally do not form solid tumors. Cancerous tumors are malignant and can spread into, or invade nearby tissues (Blog #27, Tables 6.1 and 6.2). Some cancer cells can break off and travel to distant places in the body through the blood or the lymph system and form new tumors far from the original tumor. A cancer that has spread from the place where it first started, its primary site, to another place in the body is called metastatic cancer. Diagnostic tests ranging from laboratory studies to imaging to biopsy are all clinically indicated in a cancer diagnosis (Table 6.3).
Cancer cells are also often able to evade the immune system’s organs and cells. Some cancer cells are able to “hide” from the immune system. Tumors can also use the adaptive immune system to stay alive and grow. For example, with the help of certain immune system cells that normally prevent a runaway immune response, cancer cells can sometimes prevent the immune system from killing cancer cells, a deadly paradox.
Cancers are identified by the type of cells involved and the area of the body from where they originate. The first diagnostic tests in a cancer diagnosis include biopsy and imaging ranging from photography, through nuclear scanning, and MRIs. Other more advanced diagnostic tests include the study of gene protein expression that we discussed back in Blog #28 and proteomics, the biology of the expressed proteins, to establish indicators for more accurate diagnoses of cancers. Using large databases of DNA gene expression, genomic sequencing is now involved in identifying and regulating the effects of a gene. Computerized artificial intelligence (AI) image analysis that can identify different types of cancer cells simply by scanning microscopic images is also now being used extensively in cancer diagnosis.
Besides determining the nature and type of cancer in a diagnosis, one of the most critical considerations in the clinical presentation is “staging.” This is a
determination of how advanced the cancer is relative to its spreading or metastasis beyond its original location. To determine this, a number is assigned, I through IV, to characterize the degree of spread from local to disseminated, i.e., to other tissues and/or organ systems beyond the original site. The higher the number, the more cancer has spread locally or throughout the body. This information is critical in determining a plan of treatment.