Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?
在过去的15年里，先天免疫备受关注。炎症，它的标志特征，已经被公认为几乎所有慢性疾病的潜在因素，除了像风湿性关节炎和克罗恩病这样的明显的罪魁祸首，还包括糖尿病和抑郁症，以及心脏病和中风等主要杀手。在这个十年里，与第三个主要的杀手癌症有联系的可能性受到了严格的审查。“炎症和癌症之间的联系已经转移到研究领域的中心阶段，”麻省理工学院的怀特海德生物医学研究所的罗伯特·A·温伯格(Robert a . Weinberg)指出，他在他的主要教科书《癌症生物学》(Garland Science, 2006)中强调了这一变化的重点。
这种新观点意味着，根除体内每一个癌细胞可能是不必要的。相反，抗炎癌症治疗可以防止癌前细胞癌变，或阻止现有肿瘤扩散到身体的远端部位。癌症患者也许能够存活下来，就像新药物让艾滋病患者活得更久一样。“我不认为治愈是必然的目标。加州大学旧金山分校的癌症生物学家Lisa M. Coussens评论道。“如果你能控制疾病，度过你的自然寿命，那将是一个巨大的胜利。”
近年来，大量的证据表明，慢性炎症在某些类型的肿瘤的发展过程中起着重要的作用。癌症和炎症之间的联系一直被怀疑。在1863年，著名的德国病理学家Rudolf Virchow注意到在恶性组织中存在所谓的淋巴细胞浸润(白细胞)。早在1978年，人类临床研究所和米兰大学的Alberto Mantovani观察到，先天免疫细胞倾向于聚集在一些肿瘤周围。哈佛医学院的癌症生物学家Harold F. Dvorak在1986年说，肿瘤是“不能愈合的伤口”。然而，现状却在别处。甚至在十年前，许多生物学家仍然坚持认为免疫系统不仅可以消灭病原体，而且可以清除癌变前的异常细胞。但是仔细观察肿瘤周围的微环境发现了意想不到的事情。
在1990年代末，伦敦大学的QUEEN MARY 癌症研究所的Frances Balkwill一直在研究称为肿瘤坏死因子(TNF)的细胞因子(激素样免疫信号分子), 这样命名，是因为大剂量直接注入肿瘤时，这种因子可以杀死癌细胞。但持续性低水平的TNF在肿瘤徘徊时，它的作用就大不相同了。Balkwill的实验室关闭了老鼠的TNF基因，使老鼠无法产生这种蛋白质:令他们吃惊的是，老鼠并没有感染肿瘤。她回忆说:“那真的把我们当成了鸽子中的猫。”所有研究TNF的人都被吓坏了。他们原认为这种细胞因子是一种治疗癌症的方法实际上是一种内生肿瘤启动子。
基因敲除小鼠的现成可用性，可以测试选择性关闭基因的效果，有助于突出癌症-炎症的联系。Coussens和她的同事Douglas Hanahan和Zena Werb在1999年报道说，用激活的癌症基因改造的小鼠，但是没有肥大细胞(另一种固有免疫细胞)发展出了没有进展到完全恶性肿瘤的癌前组织。2001年，杰弗里·w·波拉德(Jeffrey W. Pollard)和他在阿尔伯特·爱因斯坦医学院(Albert Einstein College of Medicine)的同事们对老鼠进行了描述，这些老鼠的基因被改造成易于患上乳腺癌的肿瘤，但它们产生的癌前组织并没有完全变恶性，除非它获得巨噬细胞的帮助。
现在，生物学家已经能够将炎症与单个信号分子的水平联系起来，为与癌变的联系提供了更有力的证据。例如，核因子-Kappa B (NF-KB)是一种复杂的蛋白质，它可以作为启动炎症基因和控制细胞死亡的主开关。随着生物学途径的发展，NF-KB是世界闻名的，已经被科技明星发现并获得专利，用于药物开发，其中包括诺贝尔奖得主戴维·巴尔的摩和菲利普·A·利特，后来成为数百万美元专利诉讼的对象。
2004年耶路撒冷希伯来大学的Yinon Ben-Neriah 、Eli Pikarsky和他们的同事报道, 通过遗传改造敲除NF-KB 或者促炎的TNF信号被关闭后，让被遗传设计为肝炎的小鼠（可以导致成肝癌）患上癌前损伤不会发展为肝癌。在后者,中和抗体阻断肿瘤坏死因子,防止其绑定癌变前的肝细胞上的受体;受体的丢失阻止了TNF触发一个分子级联，从而启动NF-KB主开关。阻断NF-KB促使癌前肝细胞开始凋亡，或程序性细胞死亡。在一项相关的研究中，迈克尔·卡琳和他在加州大学圣地亚哥分校的合作者们发现，抑制NF-KB基因的小鼠被设计成结肠炎，这可能导致结肠癌，也促进了细胞凋亡。而在炎性细胞(如巨噬细胞)中关闭通路，也会阻止肿瘤的发展。
与此同时，Coussens和她在U.C.S.F.的同事在2005年发表在《癌症细胞》上的一项研究中发现，被设计为容易患皮肤癌的小鼠体内的抗体生成B细胞的移除可以防止组织改变和血管生成，这是疾病进展的前提条件。作为病原体攻击者，B细胞产生的抗体，通过血液循环，标志病毒和细菌已被先天性免疫细胞歼灭。然而，作为对癌前组织信号的反应，抗体诱导先天系统在癌症发展中合作。一个公开的研究问题是这个过程是如何开始的。一种可能性是，癌细胞可能会向先天免疫细胞(可能是树突状细胞)发送信息，然后激活B细胞。信号可能与TOLL样受体有关，这种受体在先天免疫信息传递中已经成为重要的中介(参见Luke A. J. O ' neil的“免疫早期预警系统”;《科学美国人》,2005年1月)。
从本质上说，癌症可能会成为一种类似于风湿性关节炎的慢性疾病，这是另一种炎症性疾病。“记住，几乎没有人死于原发性癌症，”德克萨斯大学安德森癌症中心(University of Texas m.d. Anderson cancer Center)的教务长雷蒙德·杜布瓦(Raymond DuBois)说，他是癌症的抗炎药物研究人员。“病人几乎总是死于转移。”
一种抗慢性炎症的药物比杀死恶性细胞(不可避免的，包括健康的细胞)更有吸引力，它是现有化疗的结果。单独服用，这样的药物可能是良性的，可以每天使用作为预防高危患者。流行病学和临床研究表明，使用非甾体类抗炎药(非甾体抗炎药)如阿司匹林，可以延缓某些实体肿瘤的发生。 更能选择性地阻断前列腺素的产生的研究仍在进行。前列腺素是由非甾体抗炎药抑制的调控分子。特别是抑制前列腺素E2生产的药物可以抑制炎症和肿瘤生长，同时避免像Vioxx和早期NSAIDs一类的胃肠道问题等药物的心血管副作用[参见Gary Stix的《更好的目标疼痛方法》[参见]。《科学美国人》, 2007年1月)。人们还在考虑使用无所不在的他汀类药物来降低胆固醇的抗炎作用。
一组正在考虑一种激进的治疗方法，一种分子特洛伊木马。英国谢菲尔德大学的Claire Lewis和Munitta Muthana和他们的同事设计了一种药物传递方案，利用巨噬细胞的自然吸引力，使其进入肿瘤缺氧的区域。他们设计了巨噬细胞，将一种治疗性的病毒送到缺氧的肿瘤区域，这些区域对常规治疗如化疗和放疗的反应很差，因为血液供应不足。一旦巨噬细胞到达肿瘤(到目前为止在培养基中生长)，每一个巨噬细胞都会释放数千个病毒拷贝，然后感染癌细胞，然后这些细胞中的蛋白质激活每个病毒的治疗基因。然后，这个动作指示细胞-杀死毒素的合成。“巨噬细胞正在迁移到一个地方，做我们想做的事，而不是以正常的方式驱动肿瘤的发展，”Lewis说。
Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?
Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer
By Gary Stix on November 9, 2008
Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?
Editor's Note: This story, originally printed in the July 2007 issue of Scientific American, is being posted in light of two new studies showing that angiogenesis inhibitors, discussed in this article, may actually make tumors bigger, not smaller.
More than 500 million years ago a set of specialized enzymes and proteins evolved to defend our primitive ancestors against assaults from the outside world. If a microbe breached the shell of some Cambrian-era fauna, the members of this early vintage immune system would stage a savage but coordinated attack on these interlopers—punching holes in cell walls, spitting out chemical toxins or simply swallowing and digesting the enemy whole. Once the invaders were dispatched, the immune battalion would start to heal damaged cells, or if the attacked cells were too badly damaged it would put them to rest.
This inflammatory immune response worked so well that many aspects of it have been preserved during the protracted aeons of evolution. We know this to be true because studies have found that we share many of the same immune genes as the lowly fruit fly—and vertebrates and invertebrates diverged from a common ancestor in excess of half a billion years ago.
For years, immunology researchers have paid relatively little attention to this thuggish innate immune system, basically thinking of it as a crew of biochemical bouncers that pummel anything able to penetrate the tiniest opening in a living being’s skin or shell. They lavished their attention, instead, on the more advanced adaptive immune system, which can marshal antibodies and other weaponry that identify and then target an intruder with a specificity lacking in the untamed innate system.
In the past 15 years, innate immunity has come into its own. Inflammation, its hallmark characteristic, has gained recognition as an underlying contributor to virtually every chronic disease—a list that, besides obvious culprits such as rheumatoid arthritis and Crohn’s disease, includes diabetes and depression, along with major killers such as heart disease and stroke. The possibility of a link with a third major killer—cancer—has received intensive scrutiny in this decade. “The connection between inflammation and cancer has moved to center stage in the research arena,” notes Robert A. Weinberg of the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research, who has highlighted the changing emphasis in a revision of his leading textbook, The Biology of Cancer (Garland Science, 2006).
This transformation recognizes that the immune inflammatory state serves as a key mediator of the middle stages of tumor development. Cancer begins with a series of genetic changes that prompt a group of cells to overreplicate and then invade surrounding tissue, the point at which true malignancy begins. Eventually some tumor cells may break off and establish new growths (metastases) at distant sites. That much has been understood for a long time. But cancer biologists and immunologists have begun to realize that the progression from diseased tissue to full-blown invasive cancer often requires cells that normally participate in healing cuts and scrapes to be diverted to the environs of the premalignant tissue, where they are hijacked to become co-conspirators that aid and abet carcinogenesis. As some researchers have described the malignant state: genetic damage is the match that lights the fire, and inflammation is the fuel that feeds it.
In this rewriting of the textbooks, a tumor is not just a clump of aberrant cells; it also includes a support system, a tumor microenvironment, which encompasses a multitude of varying immune cell types and crisscrossing chemical signals, along with a network of blood vessels. The tumor assumes the status of an outlaw organ that exists not to pump blood or rid the body of toxins but to serve only its own ends.
This new view implies that rooting out every last cancer cell in the body might not be necessary. Anti-inflammatory cancer therapy instead would prevent premalignant cells from turning fully cancerous or would impede an existing tumor from spreading to distant sites in the body. Cancer sufferers might then be able to survive, in the same way that new drugs have let HIV patients live longer. “I don’t think a cure is necessarily the goal. It doesn’t need to be,” comments Lisa M. Coussens, a cancer biologist at the University of California, San Francisco. “If you can manage the disease and live your natural life span, that’s a huge win.”
Multiple Lines of Defense
Comprehension of the link between inflammation and cancer requires knowing how the body reacts to invaders—and how normal healing is then subverted into promoting cancer when the inflammatory state lasts too long. After you step on a nail, the bacteria that invade the sole of your foot receive a welcome from an array of proteins and white blood cells that resemble rejects from central casting for the movie Creepshow 2. Just one example: Some 20 complement proteins, so called because they complement other bodily defense mechanisms, chemically spritz pathogens until the invaders explode into a big protoplasmic mess. While the complement system slimes the area, an assemblage known in immunology textbooks as professional phagocytes—literally “expert eating cells”—goes to work.
Lacking table manners, these Pac-Man-like macrophages and neutrophils proceed to engulf and consume the uninvited guests. Other members of the attack brigade include natural killer cells, mast cells and eosinophils. Healing represents more than launching an offensive against invaders. Blood platelets involved with clotting migrate to the break in the skin from an inner layer infused with blood vessels. Enzymes direct the repair of the extracellular matrix, the protein-based mortar in which the cells are immobilized. A scab forms, the skin grows back and the whole process of inflammation ends. Sometimes, though, inflammation does not stop. Any tissue (not just skin) that is chronically inflamed because of the persistent presence of pathogens, toxins or genetic damage helps to spur illness, from heart disease to cancer.
Beyond this first layer of defense, vertebrates are equipped with additional weaponry. The adaptive system learns an invader’s specific molecular signature and then uses it as a target for killing. Among the protagonists are B cells, which produce antibody molecules able to neutralize pathogens or mark them for destruction, and T cells, which prompt infected cells to kill themselves or secrete chemicals that direct the activities of other immune players.
In recent years a body of evidence has accumulated to show that chronic inflammation can play an important role in the progression of some types of tumors from a premalignant state to full-blown disease. A link between cancer and inflammation has long been suspected. In 1863 the prominent German pathologist Rudolf Virchow noted the presence of so-called lymphoreticular infiltrate (white blood cells) in malignant tissue. As early as 1978 Alberto Mantovani of Humanitas Clinical Institute and the University of Milan had observed that innate immune cells tend to congregate around some tumors. Cancer biologist Harold F. Dvorak of Harvard Medical School remarked in 1986 that tumors are “wounds that do not heal.” The status quo, though, lay elsewhere. Even a decade ago many biologists still hewed to the idea that the immune system serves not only to eliminate pathogens but to ferret out cells that are the abnormal precursors of cancer. But a closer look at the microenvironment surrounding tumors found the unexpected.
In the late 1990s Frances Balkwill of the Institute of Cancer at Queen Mary, University of London, had been doing research on a cytokine (a hormonelike immune signaling molecule) known as tumor necrosis factor (TNF), which was named for its ability to kill cancer cells when administered directly into a tumor at high levels. But when TNF lingers as a chronic, low-level presence in the tumor, it acts very differently. Balkwill’s lab turned off the TNF gene in mice so that the rodents could not produce the protein: to their surprise, the mice did not contract tumors. “That really put us as the cat among pigeons,” she recalls. “All the people who were working on TNF as an anticancer agent were horrified. This cytokine they thought was a treatment for cancer was actually working as an endogenous tumor promoter.”
The ready availability of knockout mice, in which the effects of selectively switching off genes could be tested, helped to highlight the cancer-inflammation link. Coussens and her U.C.S.F. colleagues Douglas Hanahan and Zena Werb reported in 1999 that mice engineered with activated cancer genes but without mast cells (another type of innate immune cell) developed premalignant tissue that did not progress to full malignancy. In 2001 Jeffrey W. Pollard and his co-workers at the Albert Einstein College of Medicine described mice that were genetically engineered to be susceptible to breast cancer tumors but that produced precancerous tissue that did not turn fully malignant unless it enlisted the assistance of macrophages.
The altered picture does not completely overturn the old one. In fact, it reveals that the immune system functions as a double-edged sword. The network of molecules and cells, second in complexity only to the brain, remains a paradox: sometimes it promotes cancer; other times it hinders disease. Some types of innate immune cells, such as natural killer cells, can actually protect against tumor growth. Others may nurture a malignancy only when the microenvironment is “polarized” into an inflammatory state; when not, they may blot it out. Inflammation, moreover, produces tumors in many organs, but not all—and its link to blood-borne cancers is not well characterized.
When looking for culprits, researchers have often focused their microscopes on macrophages, which occupy a meaningful spot among the white blood cells in the tumor microenvironment. The macrophages are capable of killing tumor cells or sending out an alarm to T cells of the adaptive immune system that something is amiss. But work by Pollard and other researchers has detailed how macrophages are “reeducated” by cancer cells to do their bidding. They become factories for cytokines and growth factors that nurture tumor development.
Turning the macrophages into traitors begins when tumor cells send out help signals that attract cells that become macrophages once they reach the tumors. Inside the tumors, proliferating cells grow so quickly that they begin to die for lack of oxygen. A combination of hypoxia and messages from the tumor cells initiates a process whereby the newly arrived macrophages assume their bad-body identity as tumor promoters. Cancer biologists give the name tumor-associated macrophages to these mutineers that congregate in and around the tumor.
Biologists have now been able to follow the inflammation link down to the level of individual signaling molecules, providing harder evidence for a connection to carcinogenesis. For example, nuclear factor-kappa B (NF-KB) is a complex of proteins that acts as a master switch for turning inflammation genes on and for controlling cell death. As biological pathways go, NF-KB’s is world-famous, having been discovered and patented for use in drug development by scientific stars that include Nobelists David Baltimore and Phillip A. Sharp and having subsequently become the object of multimillion-dollar patent litigation.
In 2004 Yinon Ben-Neriah and Eli Pikarsky of the Hebrew University of Jerusalem and their colleagues reported that mice engineered to develop hepatitis (which can cause liver cancer) contracted precancerous lesions that did not progress to full malignancy when NF-KB was curtailed through a genetic alteration or when the proinflammatory TNF signaling molecule was shut off. In the latter group, a neutralizing antibody blocked TNF and prevented it from binding to a receptor on the premalignant liver cells; loss of the receptor prevented the TNF from triggering a molecular cascade that turns on the NF-KB master switch. Blocking NF-KB prompted the precancerous liver cells to initiate apoptosis, or programmed cell death. In a related finding that year, Michael Karin and his collaborators at the University of California, San Diego, found that inhibiting NF-KB in mice engineered to develop colitis, which can lead to colon cancer, also promoted apoptosis. And shutting down the pathway in inflammatory cells, such as macrophages, deterred tumor development as well.
So far the clearest evidence of a link between cancer and inflammation is the data demonstrating that inflammation encourages the conversion of precancerous tissue to full malignancy for many cancers. But the biological response may also be involved in initiating the disease and in advancing metastasis. Infections with Helicobacter pylori bacteria induce inflammation that greatly increases the risk of gastric cancer, and the hepatitis C virus can bring on liver cancer, to name just two cancers. Pathogens may also generate free radicals, which can damage DNA. But although inflammation may be involved from the outset, few studies have shown yet that an inflammatory condition actually alters DNA to provide the initiating spark.
The case for a role in metastasis is stronger—and recent studies lend credence to this hypothesis. Karin’s group reported in the April 5 Nature that inflammation, not genetic changes in cancer cells, spurs metastasis in mice engineered to acquire prostate cancer. The research suggests that a cytokine produced by inflammatory cells near a prostate tumor induces tumor cells to decrease production of a protein that blocks metastasis. This result, Karin notes, may explain the puzzling observation that cutting into tumors, such as for a prostate biopsy, sometimes seems to encourage metastasis. If he is correct, the inflammation generated by the intervention could be at fault. Around the same time, Pollard’s group reported in Cancer Research on a study in mice that observed that macrophages accompany breast tumor cells in their migration toward blood vessels that will transport them to remote sites, all the while sending chemical messages to their partners.
The innate immune system has received the most attention in explorations of how inflammation might cause cancer. As with innate immunity, the adaptive immune system—the T cells and antibodies produced by B cells that target specific molecules on invading cells—contributes to pathology or may also fight against it. For decades, immunotherapies designed to enhance T cell responses against cancer have been explored, though often with disappointing results.
Furthermore, an emerging picture has begun to reveal an intricate cross talk between innate and adaptive immune cells that may participate in the promoting of malignant disease. Researchers working on cancer vaccines may need to take account of these interactions in designing their treatments if they are ever to prove effective. One study showed that ovarian tumors produce a signaling molecule that serves to attract regulatory T cells, a subclass of adaptive immune cells responsible for quieting other T cells [see “Subduing Suppressors,” by Lisa Melton; Scientific American, December 2002].
Meanwhile Coussens and her colleagues at U.C.S.F. found in a 2005 study published in Cancer Cell that the removal of antibody-making B cells from mice engineered to be prone to skin cancer prevented the tissue changes and angiogenesis that are prerequisites for disease progression. In their normal role as pathogen fighters, B cell–produced antibodies circulate through the bloodstream and mark viruses and bacteria for destruction by innate immune cells. In response to a signal from precancerous tissue, however, the antibodies induce the innate system to collaborate in cancer development. An open research question is how this process starts. One possibility suggests that a cancer cell may send a message to innate immune cells, perhaps dendritic cells, that then activate B cells. Signaling may involve toll-like receptors, which have emerged as prominent intermediaries in innate immune messaging [see “Immunity’s Early Warning System,” by Luke A. J. O’Neill; Scientific American, January 2005].
The recognition that cancer is more like an organ than just a clump of cells with DNA mutations in cell nuclei may also explain why some of the previous approaches to chemotherapy have met with limited success. “People have taken cells and then transformed them in culture and stuck them into animals,” Pollard says. “They grow as little balls. They do certain things there. But they are not complex tissues, whereas a naturally occurring tumor is a very complex tissue.”
Instead of just killing cancer cells—the goal of current drug therapies and radiation—new approaches may supplement existing drugs by slowing inflammation. Without the involvement of macrophages and other innate cells, the premalignant tissue would remain in check.
Cancer could, in essence, become a chronic disease akin to rheumatoid arthritis, another inflammatory condition. “Keep in mind almost no one dies of primary cancer,” says Raymond DuBois, provost of the University of Texas M. D. Anderson Cancer Center and a researcher of anti-inflammatory agents for cancer. “A patient almost always dies from a metastasis.”
A pharmaceutical against chronic inflammation represents a more alluring proposition than massacring malignant cells (and, unavoidably, healthy ones), a consequence of existing chemotherapies. Taken alone, such an agent might be benign enough to use every day as a preventive for high-risk patients. Epidemiological and clinical studies have shown some promise for the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin to stave off the onset of some solid tumors. Investigations continue on more selective blocking of the production of prostaglandins, the regulatory molecules that are curtailed by NSAIDs. In particular, drugs that inhibit production of prostaglandin E2 may curb inflammation and tumor growth, while avoiding the cardiovascular side effects of drugs such as Vioxx and the gastrointestinal problems of the earlier class of NSAIDs [see “Better Ways to Target Pain,” by Gary Stix; Scientific American, January 2007]. The anti-inflammatory effects of the ubiquitous statins used to lower cholesterol are also being contemplated.
Some treatment options already exist. The drug Avastin inhibits production of the angiogenesis- promoting VEGF, although oncologists must contend with other molecules in the tumor microenvironment that promote blood vessel growth. Drugs developed for more familiar inflammatory diseases may also fight cancer—and these medicines might be combined into HIV-like drug cocktails, that also include angiogenesis inhibitors and cell-killing agents.
Inhibitors of TNF have received approval for treatment of rheumatoid arthritis, Crohn’s disease and other disorders and are now in clinical trials for both solid tumors and blood cancers. The drug Rituxan, a monoclonal antibody that represses B cells in rheumatoid arthritis and B cell lymphoma, might prevent the inflammatory response that fuels formation of solid tumors. Other cytokines and related molecules (IL-6, IL-8 and CCL2, among others) are also potential targets, as is NF-KB.
Some existing compounds, including NSAIDs and even one found in the spice turmeric, exert at least some of their effects by inhibiting NF-KB. But major pharmaceutical laboratories are investigating highly selective inhibitors of this molecular linchpin, many of them targeted at the enzymes (such as I-KB kinase) that regulate NF-KB activity.
A Chemical Trojan
One group is contemplating a radically ambitious treatment, a molecular Trojan horse of sorts. Claire Lewis and Munitta Muthana of the University of Sheffield in England and their colleagues have designed a drug delivery scheme that takes advantage of the natural attraction of macrophages to the oxygen-starved areas in tumors. They have engineered macrophages to deliver a therapeutic virus to hypoxic tumor regions, which respond poorly to conventional treatments such as chemotherapy and radiation because of an insufficient blood supply. Once the macrophages arrive in a tumor (grown in culture so far), each one releases thousands of copies of the virus, which then infect the cancer cells, after which a protein in those cells activates the therapeutic gene in each virus. This action then directs synthesis of a cell-killing toxin. “The macrophage is migrating into a site and doing what we want it to do rather than driving tumor development in a normal way,” Lewis says.
The exact outlines of an anti-inflammatory strategy against cancer have yet to be elucidated. Tweaking immune cells that form a defensive barrier against pathogens bears its own risks. “It’s a very complicated issue,” DuBois notes. “If you magically shut down the immune system, you will have problems with opportunistic infections, just like with AIDS.” Use of TNF blockers in other inflammatory disorders has been linked to tuberculosis and other infections, even potentially lymphoma. Moreover, inhibiting the NF-KB pathway can paradoxically promote cancer in some instances. Constraining NF-KB can at times lead to tissue damage and a process of abnormal regeneration of that tissue that can foster cancer.
Still, it seems likely that a new generation of anti-inflammatory agents will join the chemotherapeutic arsenal. Chronic diseases—and their underlying inflammatory conditions—are hallmarks of an aging population. “We’re all a little bit overinflamed,” Pollard observes. Treating the smoldering embers that surround the tumor rather than just mutant cells could make cancer a disease we can live with.