223 COMMENTARY The Use of Inflammation by Tumor Cells 1 Jose-Ignacio Arias, M.D., Ph.D. 2 Marı´a-Angeles Aller, M.D., Ph.D. 2 Jaime Arias, M.D., Ph.D. 1 Servicio de Cirugı´a General, Hospital Monte Naranco, Oviedo, Asturias, Spain. 2 Ca´tedra de Cirugı´a, Departamento de Cirugı´a I, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. ancer is malignant, because tumor cells invade neighboring tis- Csues and survive in these ectopic sites. This invasion permits them to enter into the circulation, from which they can reach distant organs and, eventually, form secondary tumors, called metastases.1 The classical metastatic cascade encompasses intravasation by tumor cells, circulation of these cells in lymph and blood vascular systems, arrest in distant organs, extravasation, and growth into met- astatic foci.1,2 However, the tumor cells can adopt a great variety of phenotypes; and, due to this plasticity of the malignant cells; it has been proposed that a more dynamic view is needed for the metastatic cascade.2,3 Invasion and metastases are not unique for cancer, because they also occur during embryonic development, in adult tissue mainte- nance, and in many noncancerous diseases, such as in repair pro- cesses.1,2 In relation to the latter, tumor cells have been described as wounds that do not heal.4 Both tissue repair, a beneficial process, and tumor formation, a harmful process, share some molecular mechanisms that can be ascribed to inflammation.1,2,5 Therefore, in one sense, it is possible that inflammation is shared by both processes: tissue repair and tumor formation. The Possible Trophic Significance of the Inflammatory Response in Tissue Repair To integrate the different alterations that are produced after injury by mechanical energy (posttraumatic inflammation), we consider that a response based on the successive functional predominance of the Supported by grant GE-EJS01-04 from the Princi- nervous, immune, and endocrine systems would be produced. This pado de Asturias, Education and Culture Council. hypothesis implies that the final and prevalent functions of these Address for reprints: Jaime Arias, M.D., Ph.D., systems may represent the consecutive phases of the response to Ca´tedra de Cirugı´a, Facultad de Medicina, Univer- stress, all of which may have trophic significance.6–8 sidad Complutense, Pza. Ramo´n y Cajal s.n., In the nervous phase, ischemia-reperfusion, which causes inter- 28040 Madrid, Spain; Fax: (011) 34 913947115; stitial and cellular edema, is produced. Both types of edema may E-mail: [email protected] represent an ancestral mechanism to feed the cells by diffusion. Received October 31, 2004; revision received Feb- During the immune phase, the tissues are infiltrated by inflammatory ruary 14, 2005; accepted March 3, 2005. cells and bacteria. Hence, extracellular digestion, by enzyme release © 2005 American Cancer Society DOI 10.1002/cncr.21165 Published online 3 June 2005 in Wiley InterScience (www.interscience.wiley.com). 224 CANCER July 15, 2005 / Volume 104 / Number 2 TABLE 1 Inflammatory Response and Tumor Evolution Inflammatory response Tumor cell Nervous phase Immune phase Endocrine phase Benign -Ischemia-reperfusion -Infiltration by inflammatory cells -Extracellular matrix Induces inflammatory response or -Angiogenesis host reaction -Cellular proliferation Desmoplasia Malignant -Hypoxic tumoral cells -Leukocyte tumoral phenotype -Vascularized malignant primitive tumor Adopts an inflammatory -Anaerobic glycolytic metabolism -Anaerobic glycolysis -Oxidative phosphorylation phenotype -Revascularization -Proinflammatory gene expression -Vasculogenic mimicry -Reperfusion injury -Migration and invasion -Angiogenic metastasis -Oxidative stress -Lymph node metastasis -Cachectic syndrome -Nutrition by diffusion -Micrometastasis (preangiogenic or “dormant”) -Nutrition by digestion, (extracellular and intracellular) (fermentation) and intracellular digestion by phagocy- called malignant or cancers that invariably kill their tosis may be associated with a hypothetical trophic host if untreated.1 The invasive capacity of cancers is capacity for the neighboring cells. Finally, in the late reflected in the classic metastatic cascade, which is or endocrine phase, nutrition mediated by the blood staged according to the volume of the primary tumor capillaries is established.7 In these three successive and its depth of invasion (T stage), the number and phases, the inflammatory response progresses from the volume of occupied lymph nodes as well as inva- an anaerobic metabolism (ischemia), through a me- sion through their capsule (N stage), and the presence tabolism characterized by defective oxygen use (reper- of distant metastases (M stage).1 However, if the pre- fusion, oxidative burst, and heat hyperproduction), viously described functional concept of inflammatory and, finally, to an oxidative metabolism (oxidative response is applied to tumor evolution, then this may phosphorylation) with correct use of oxygen to pro- help us to better understand the mechanisms that duce usable energy. This type of metabolism is char- govern their invasive capacity and to obtain a more acterized by a large production of adenosine triphos- dynamic view of the metastatic cascade. phate (ATP), which is used to drive specialized The tumor benign cells seem to be able to induce multiple cellular processes.7,9,10 an inflammatory response in the host. Therefore, it is Because the nervous, immune, and endocrine possible that the host may participate in establish- phases of the inflammatory response progress from ment of the tumor by a process called desmoplasia, ischemia to the development of an oxidative metabo- consisting of fibroblastic cells and extracellular matrix lism, it also is tempting to speculate on whether the as inflammation and immune response, represented body reproduces the successive stages by which life by lymphocytes, macrophages, and dendritic cells, passes from its origin without oxygen until it develops and as angiogenesis, evidenced by newly formed an effective, although costly, system for the use of blood and lymph vessels.1 Essentially, all of the ele- oxygen every time we suffer posttraumatic acute in- ments that constitute the inflammatory response par- flammation.9,10 Likewise, the successive expression of ticipate in this “host reaction” that, thus, may have a these three functional systems during embryonic de- trophic purpose for the tumor cells7,9 (Table 1). velopment and also during the evolutionary develop- The nutritional importance of this host cell reac- ment of our species may explain why the inflamma- tion for tumor cells, manifested by leukocytes, blood tory response is a ubiquitous mechanism that is vessels, and stroma, would explain why these host common to multiple diseases, because it is an integra- elements, although more abundant in some types of tor of the ontogeny and phylogeny.7 cancer than in others, are omnipresent.1 However, when tumor cells reach higher grades of malignancy, Inflammatory Response and Tumors their invasive capacity seems to be more of a reflection Tumors can be noninvasive or benign, because they of the new capacity to express the inflammatory re- are cured easily by simple removal, and invasive—also sponse than to induce it in the host. In this hypothet- Inflammation and Cancer/Arias et al. 225 ical circumstance, the successive phases that have turn, this system can be regulated by hypoxia and/or been described in the posttraumatic inflammatory re- reoxygenation.11 More specifically, the expression of sponse would be expressed by tumor cells and would inducible genes leading to the synthesis of cytokines, express their evolution with invasion and metastases chemokines, adhesion molecules, and autacoids relies (Table 1). on transcription factors; and, among the primary tran- Thus, the first evolutive or nervous phase would scription factors, NF-␬B plays a central role in the be characterized by the ischemia-reperfusion phe- regulation of inflammatory mediators.17 nomenon. In this sense, the tumor cell seems to adopt Activation of the general stress-responsive tran- an ischemic phenotype (hypoxic),11,12 which, when it scription factors, such as NF-␬B, in the tumor cells11 comes into contact with oxygen, undergoes a process may imply their transition to a hypothetical phase of revascularization. The transcriptional response to called an immune phase, because this may be associ- hypoxia relies on multiprotein complexes to regulate ated with proinflammatory gene expression. Hence, several transcription factors, the most well studied of tumor cells may usurp key mechanisms by which in- which is hypoxia inducible factor-1 (HIF-1), which flammation interfaces with cancer to further their col- that enhances the expression of hypoxia-responsive onization of the host.18 genes and, thus, allows improved cell survival in con- The association between inflammation and cancer ditions of limited oxygen availability.11,12 can be established by studying the influence of inflam- Hypoxic tumor cells change to an anaerobic gly- matory cells in tumoral progression. Currently, the tu- colytic metabolism as the main source of ATP, become mor microenvironment, which is orchestrated largely by resistant to apoptosis (programmed cell death), inflammatory cells, is considered an important partici- present inhibition of differentiation, and become pant in the neoplastic process, because it may foster the more likely to migrate to less hypoxic areas.12 More- spread of tumors.18 In addition, solid tumors are infil-