© Beth Ponticello

One problem with the current war on cancer is that much of it focuses on destroying the malignant cell itself while paying little attention to some of cancer's allies that are more prone to attack.

Cancer undoubtedly starts and ends with the malignant cell, and through tremendous efforts, we have identified many of the molecular and cellular attributes that define such cells. Genetic changes that lead to activation of oncogenes and/or inactivation of tumor suppressors result in aberrant control of cell proliferation and death, endowing the malignant cell with migratory and invasive properties. These changes, however, represent only the initial spark that ignites cancer's fire. Without fuel a fire cannot spread, and in cancer's case, inflammation feeds the blaze. Current cancer therapies that induce necrosis and inflammation may further fan the flames.


© 2005 Nature Publishing Group

Two pathways lead to NF-κB activation. In the...


One of the problems in the inflammation-cancer field was the absence of well-defined molecular mechanisms linking chronic inflammation to tumor initiation and promotion. As is often the case, the solution came from another field. NF-κB, the transcription factor identified by David Baltimore and colleagues in 1986, has caught the attention of investigators interested in cell signaling and immunity. NF-κB is rapidly activated in response to numerous proinflammatory stimuli, as well as bacterial or viral infections. Once activated, it contributes to expression of many genes, whose products regulate immune and inflammatory responses.

Early connections between NF-κB and cancer were realized when its p65 subunit was identified as RelA, a relative of v-Rel, the oncogene of the reticuloendoblastosis virus. Thus, much of the early research sought out oncogenic mutations that would result in NF-κB's constitutive activation in malignant cells. A few such mutations were found, but were relatively rare and failed to explain the rather ubiquitous NF-κB activation in most types of cancer.1

My own interest in studying the NF-κB-cancer connection started with our observation, made simultaneously with the labs of Baltimore, Inder Verma, and Albert Baldwin, that NF-κB activation inhibits programmed cell death.2 Diminished apoptosis is an important contributor to malignancy, and infections and inflammation result in activation of NF-κB. So, the proposal that NF-κB provides a molecular link between inflammation and cancer was not too far-fetched.1

The challenge was to critically test this hypothesis in a convenient animal model. While it's impossible to completely inactivate NF-κB in the laboratory mouse, two general approaches allow its conditional inhibition in a given cell type. The first is based on conditional expression of a mutant form of a specific NF-κB inhibitor, IκBα, that is resistant to phosphorylation-induced degradation – the so-called IκB super-repressor. IκB-SR expression retains NF-κB in the cytoplasm and selectively inhibits NF-κB-driven gene expression. The second approach is based on conditional inactivation of the IκB kinase (IKK) complex, responsible for signal-induced phosphorylation that leads to IκB degradation and NF-κB activation. Through inducible expression of IκB-SR in hepatocytes, Eli Pikarsky, Yinon Ben-Neriah, and colleagues tested the effect of NF-κB inhibition on the development of a type of liver cancer caused by chronic inflammation.


Inhibiting NF-κB in older animals already exhibiting chronic liver inflammation greatly retarded cancer development – not because inflammation was prevented, but rather through the accelerated death of preneoplastic hepatocytes.3 We obtained similar results using cell type-specific deletion of the IKKβ gene in intestinal epithelial cells and a model of inflammation-associated colorectal cancer.4 Preventing NF-κB activation in intestinal epithelial cells dramatically inhibited tumor development, again by accelerating the death of preneoplastic cells.

We also examined the effect of selective interference with NF-κB activation in macrophages and neutrophils, two cell types that do not undergo malignant conversion in inflammation-associated cancers but are likely to contribute to their development. In this case we also observed inhibition of tumor development in epithelial cells but due to a different cause. Here, inhibiting NF-κB prevented production of cytokines and chemokines stimulate the growth of preneoplastic epithelial cells.

These studies not only established NF-κB's role in linking chronic inflammation to tumor development but also indicate two distinct mechanisms through which NF-κB promotes carcinogenesis. In the epithelial cell that had undergone malignant conversion, NF-κB inhibits apoptosis. At the same time, NF-κB in inflammatory cells provides early malignant epithelial cells with a variety of growth factors to accelerate tumor growth and progression.

<p>Michael Karin</p>

UCSD Health Sciences Communication

The two types of experimental cancer described above belong to a group representing 15% to 20% of all cancers, in which underlying causes of chronic inflammation are easily detected. But what about the remaining cancers in which an underlying chronic inflammation or infection is not known to exist? Does inflammation play a causative role there as well?

To answer this question we used a model of chemically induced liver cancer in which no chronic inflammation is deliberately induced. Here, conditional deletion of IKKβ in either hepatocytes or inflammatory cells produced surprising results. Instead of reducing cancer load, selective NF-κB inactivation in hepatocytes greatly enhanced tumor development, but additional deletion of IKKβ in inflammatory cells resulted in a dramatic reduction in tumor number and size.5

We propose that in tissues such as the liver, excess cell death caused by inhibition of NF-κB and exposure to a cytotoxic carcinogen triggers compensatory cell proliferation. Nonetheless, the driving force is NF-κB in inflammatory cells, which provides surviving epithelial cells – including cells that harbor potentially oncogenic mutations – with growth factors. We propose that the release of cellular constituents during necrotic cell death drives this NF-κB activation.5


These studies, I believe, establish inflammation's role in providing and maintaining the fuel for many types of cancer, even those not associated with preexisting inflammation. And I think they bear relevance for cancer therapy as well. Most current anticancer drugs, as well as therapeutic radiation, kill tumors by inducing necrosis rather than pure apoptosis. And unlike apoptosis, necrosis results in activation and chemotactic attraction of additional inflammatory cells. This results in production of vast amounts of proinflammatory cytokines and chemokines that enhance the proliferation of surviving malignant cells. A single round of chemotherapy or radiotherapy is never 100% efficient, after all.

High levels of necrosis are commonly associated with rapidly growing tumors and are considered a sign of poor prognosis. Thus this cycle of necrosis, inflammation, and regeneration can be a major driving force in tumor development and progression. In the future, we need to find practical and selective ways to block this inflammatory response and combine anti-inflammatory drugs with preexisting chemotherapeutic and radiotherapeutic procedures. Thus, by attacking not only the malignant cell, but also inflammation, we should achieve much better survival rates than currently possible.

Mounting Evidence

A cancer–inflammation connection has long been suspected. Some have pegged its origins on Galen of ancient Greece. Modern connections were made in the 19th century by Rudolph Virchow.1 Yet this work was nearly forgotten until Harold Dvorak compared tumors to wounds that never heal.2 Later, Alberto Mantovani and colleagues implicated inflammatory chemokines in cancer growth and its spread through macrophage recruitment,3 whose role in cancer progression was demonstrated by Pollard.4

Fran Balkwill showed that the major pro-inflammatory cytokine tumor necrosis factor (TNF) may actually operate as a tumor promoter,5 and Ray Dubois and Mark Taketo demonstrated the importance of the pro-inflammatory enzyme cyclo-oxygenase-2 (COX2) and some of its products (the prostaglandins) in tumor progression and angiogenesis.6 Further, epidemiological studies demonstrate that chronic infections and inflammatory conditions such as hepatitis, gastritis, and chronic silicosis or asbestosis are major risk factors for cancer.7

Why, then, is so much effort focused on the malignant cell rather than the inflammatory cell?

"Inflammation and cancer: back to Virchow?" Balkwill F, Mantovani A, Lancet , 2001 Vol 357, 539-45"Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing," Dvorak HF, N Engl J Med , 1986 Vol 315, 1650-9"The origin and function of tumor-associated macrophages," Mantovani A, Immunol Today , 1992 Vol 13, 265-70"Tumour-educated macrophages promote tumour progression and metastasis," Pollard JW, Nat Rev Cancer , 2004 Vol 4, 71-8"Tumor necrosis factor or tumor promoting factor?" Balkwill F, Cytokine Growth Factor Rev , 2002 Vol 13, 135-41"Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2," Gupta RA, Dubois RN, Nat Rev Cancer , 2001 Vol 1, 11-21"Infections as a major preventable cause of human cancer," Kuper H, J Intern Med , 2000 Vol 248, 171-83

Michael Karin is a professor of pharmacology at the University of California, San Diego School of Medicine and an American Cancer Society Research Professor. He is a cofounder of Signal Pharmaceuticals (now Celgene), and was elected this year to the National Academy of Sciences.

Interested in reading more?

Magaizne Cover

Become a Member of

Receive full access to digital editions of The Scientist, as well as TS Digest, feature stories, more than 35 years of archives, and much more!
Already a member?