Chronic Inflammation and Cancer: The Role of the Mitochondria

Accumulating evidence shows that chronic inflammation can promote all stages of tumorigenesis, including DNA damage, limitless replication, apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, and tissue invasion/metastasis. Chronic inflammation is triggered by environmental (extrinsic) factors (eg, infection, tobacco, asbestos) and host mutations (intrinsic) factors (eg, Ras, Myc, p53). Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. However, the precise molecular mechanisms involved and the interconnecting crosstalk between pathways remain incompletely understood. We review the evidence implicating a strong association between chronic inflammation and cancer, with an emphasis on colorectal and lung cancer. We summarize the current knowledge of the important molecular and cellular pathways linking chronic inflammation to tumorigenesis. Specifically, we focus on the role of the mitochondria in coordinating life- and death-signaling pathways crucial in cancer- related inflammation. Activation of Ras, Myc, and p53 cause mitochondrial dysfunction, resulting in mitochondrial reactive oxygen species (ROS) production and downstream signaling (eg, NFκB, STAT3, etc.) that promote inflammation- associated cancer. A recent murine transgenic study established that mitochondrial metabolism and ROS production are necessary for K-Ras–induced tumorigenicity. Collectively, inflammation-associated cancers resulting from signaling pathways coordinated at the mitochondrial level are being identified that may prove useful for developing innovative strategies for both cancer prevention and cancer treatment.

Introduction

Virchow is credited with suggesting the causal link between inflammation and cancer in the 19th century.[1] He based his conclusion on the astute observation that tumors often developed in the setting of chronic inflammation and that inflammatory cells were present in tumor biopsy specimens. Accumulating evidence that has emerged in the last decade or so has shed light on the underlying mechanisms accounting for the strong association between chronic inflammation and each step of tumorigenesis.[reviewed in 2-8] Notably, nearly 90% of all cancers are due to environmental factors and somatic mutations, whereas causal germ-line mutations are infrequent.[6] Nearly 20% of cancer deaths worldwide are attributed to chronic infection and/or inflammation, with gastrointestinal and lung cancers accounting for a substantial portion of the total burden.[1,9] An estimated 30% of cancers may be linked to exposure to tobacco and/or other airborne pollutants, and 20% can be attributed to chronic infections.[9] In general, a normal adaptive immune response is anti-tumorigenic; however, dysregulated innate and/or adaptive immune responses can be pro-tumorigenic. Human neutrophils can induce malignant transformation, which suggests that phagocytic cells are carcinogenic.[10] Mantovani et al[3,4] proposed that genetic instability resulting from cancer-related inflammation represents the seventh hallmark of tumorigenesis, in addition to the six proposed by Hanahan and Weinberg[11] (limitless replication, sustained angiogenesis, evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, and tissue invasion/metastasis).

In this review, we summarize the current knowledge supporting the association between chronic inflammation and cancer, highlighting the information that has been published since our 2002 ONCOLOGY review.[2] We then review the emerging evidence regarding important molecular and cellular pathways that link chronic inflammation to cancer. Emphasis will be placed on the pivotal role of the mitochondria in coordinating life- and death-signaling pathways important in inflammation-associated cancer. Collectively, the studies we review are revealing the crucial mechanisms that underlie inflammation-associated cancer and that may prove useful for developing novel cancer preventative and therapeutic strategies.

TABLE 1

Cancers Associated With Chronic Inflammation

Cancers Associated With Chronic Inflammation

Internal server error