The Inflammation – Cancer Connection

Inflammatory cells and mediators are an essential component of the tumor microenvironment (TME). Figure 1 provides a schematic representation of pathways connecting inflammation, carcinogenesis and tumor progression [1–3]. Selected smoldering inflammation increases the risk of developing cancer. An example of this extrinsic pathway is provided by ulcerative colitis and colorectal cancer. Obesity as a risk factor of cancer can be seen in this same perspective. Tumors epidemiologically unrelated to overt inflammatory conditions have inflammatory cells and mediators in their TME. For instance macrophages are a component of the TME in breast cancer and promote growth and metastasis [4, 5]. Moreover, macrophage infiltration is associated with prognosis in triple negative breast cancer and with activation of the kinase MER TK which drives epithelial to mesenchymal transition [6]. The inflammatory component of the TME is complex (Fig. 1) and contributes to virtually all aspects of tumor progression [7]. In addition to inflammatory cells, components of the humoral arm of innate immunity are present in the TME and have recently emerged as important drivers of tumor progression. In particular, genetic evidence suggests that complement contributes to tumor progression [8, 9]. Indeed the humoral pattern recognition gene PTX3 has been shown to be an extrinsic oncosuppressor gene, acting as a regulator of complement-driven inflammation in preclinical models and selected human tumors [8]. Moreover, within the same histological type [10], tumors are characterized by widely different TME. For instance, in colorectal cancer four TME phenotypes have been identified [10].

Figure 1.

A schematic representation of the connection between inflammation and cancer

Dissection of the role and diversity of cancer-related inflammation may pave the way to improving on current immunotherapy strategies and may impact on diagnosis and prevention [7, 11]. The remarkable protection against incidence of and mortality by lung cancer observed in over 10,000 patients treated with anti-IL-1β mAb illustrates the importance and potential of tumor promoting inflammation.

This Special Issue of The FEBS Journal provides the reader with views of the connection between inflammation and cancer stemming from different perspectives. The present series of contributions, in addition to summarizing the state of the art of the field, provides an insight into potential lines of development at a time when, for instance, myeloid cells are a prime target to expand and complement the current immunotherapy armamentarium.

Tumor-associated myeloid cells (TAMCs), in fact, take center-stage in this Special Issue. The transition from antitumor to protumor activities in these cells poses a distinct challenge to understanding and combating cancer; and recent efforts have focused on elucidating the molecular underpinnings of this transition, and on targeting TAMCs in cancer therapy. Peter Murray focuses on the factors and signaling pathways that promote the protumor activities of tumor-associated macrophages [12]. His review also describes the present limitations of any therapy aimed at depleting macrophages from tumors [12]. Pascale Jeannin and colleagues review the signals that regulate functional plasticity in macrophages, while focusing on three key differentiation factors: Macrophage colony-stimulating factor (M-CSF), Interleukin 34 (IL-34) and Granulocyte M-CSF (GM-CSF) and their roles within the TME [13].

Metabolic rewiring has emerged as another modulator of macrophage function, and as Mazzone, Menga and Castegna argue, delineating the distinct metabolic profiles of antitumor and protumor macrophages could lead to more targeted and efficient therapies [14]. Their review covers metabolic signaling in the TME and highlights key metabolites and pathways involved in the adaptation of tumor-associated macrophages during tumor growth and metastasis [14]. Antonio Sica and colleagues provide an in-depth look at the metabolic reprogramming of TAMCs and its effects on gene regulatory networks [15]. In the second part of their review, the authors examine the current therapeutic approaches that combine immune checkpoint inhibitors with drugs targeting metabolic pathways in TAMCs [15]. The review by Jo Van Ginderachter and colleagues brings into perspective the current strategies employed to limit the proliferation of tumor-associated macrophages as well as several newly discovered surface markers that, if targeted efficiently, could make the transition from pre-clinical to clinical studies [16]. Carola Ries and colleagues focus on the development of TAMC-targeting drugs currently being clinically evaluated [17]. The authors highlight four pharmacological strategies aimed at depleting TAMCs from tumors, blocking their recruitment, boosting their antitumor activities or enhancing the activation of tumor cell phagocytosis. The review thoroughly details each strategy, its targets as well its advantages and limitations [17].

Hepatocellular carcinoma (HCC) is a typical example of an inflammation-driven cancer. While chronic hepatitis B or C virus infections are considered the leading cause of HCC, non-alcoholic fatty liver disease (NAFLD) – strongly associated with obesity - is another risk factor. The review by Tim Greten and colleagues highlights the intrinsic (i.e. hepatocyte-specific processes) and extrinsic (i.e. immune-driven processes) mechanisms which promote the transition from NAFLD to hepatic malignancy [18].

We end this Special Issue with three reviews covering the factors and processes that impact tumor cell dissemination and metastasis. Zena Werb and colleagues provide an in-depth look at the interactions between immune cells and disseminated tumor cells during the post-dissemination phase of metastasis [19]. John Hamilton and colleagues review the mounting evidence supporting a role for neutrophils and their major growth factor, granulocyte colony stimulating factor (G-CSF), in breast cancer progression to metastasis [20]. The non-cellular components of the TME may also contribute to tumor cell dissemination and metastasis, as Varol and Sagi highlight in their review [21]. They focus on the interplay between tumor-associated macrophages and neutrophils with the extracellular matrix and how this interaction shapes the TME and promotes tumor growth and dissemination [21].

We thank the authors for these excellent contributions and we hope you find these reviews interesting and informative.