TGF-β and tumors  an ill-fated alliance

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Mechanisms of host defense can form an unwitting alliance with tumor cells to promote tumor progression, invasion, and dissemination to distant sites. By secreting TGF-β, an immunoregulatory molecule designated for both promoting inflammation and dampening immune responses, the tumor tricks the host into supporting its expansion and survival. TGF-β not only recruits leukocytes to secrete chemokines, growth factors, cytokines, and proteases in support of a tumor-friendly niche but also in a context-specific manner, incapacitates the emergent immune response. As a profound immunosuppressant, TGF-β, both directly and through the generation of regulatory T cells, blunts immune surveillance, favoring tumor escape. Collectively, the ability of the tumor to hijack these host defense pathways can tip the balance in favor of the tumor.

Introduction

Tumorigenesis, a complex, multigenic process, generally occurs as cells acquire abnormal resistance to growth inhibition, proliferate autonomously, promote angiogenesis, invade, and/or metastasize. Cancers thus arise when somatic cells become subjugated to pro-oncogenic signals, eluding tumor suppressor mechanisms. Although host antitumor defense revolves around immune-mediated mechanisms of recognition and removal, paradoxically, in addition to immune surveillance, inflammation may actually promote tumor progression [1].

The link between inflammation and cancer is well-recognized and chronic wound and inflammatory states can be considered risk factors for cancer development. Since the observations made many years ago that the tumor microenvironment resembles normal wound healing, it has been proposed that tumor stroma is ‘normal wound healing gone awry’ [2]. Recapitulation of normally reparative processes within the tumor milieu may have a powerful inductive influence on cellular transformation and underlie tumor engraftment, invasion, and/or metastasis [3, 4]. Normal growth and development can be deviated by factors generated during overzealous or persistent inflammation, whether in response to tumor antigens (TAs), pathogens, or other danger signals. Infiltrating inflammatory cells produce a myriad of chemokines, growth factors, angiogenesis factors, damaging oxidant-generating enzymes, and proteases that may encourage tumor growth and invasion. Whereas inflammatory molecules such as NFκB2/p100 overactivate the developmental pathway and dysregulated signaling networks can trigger malignant growth [5], other inflammatory molecules also profoundly influence tumorigenesis. One such factor with recognized involvement in inflammation, inflammatory pathogenesis, and tumorigenesis is TGF-β [6].

In the context of a malignant niche, tumor cells themselves secrete TGF-β, as well as the stromal cells and infiltrating immune cells (Figure 1), and the increasingly TGF-β-enriched environment profoundly alters the outcome of the contest between host and tumor. Evidence supports a role for genetic mutations and aberrant TGF-β signaling pathways in cancer risk [7, 8], outside the scope of this review. Beyond the establishment of primary tumors, most cancer-related deaths stem from metastasis, which requires transformed cells to enter the vasculature, then breach the endothelium to extravasate and establish a new metastatic outgrowth, and leukocyte infiltrates have been temporally and spatially linked to basement membrane breach and tumor cell egress [4]. Continuing efforts to pinpoint genes linked to these events revealed four genes that synergistically promote tumor progression, notably, epiregulin, matrix metalloproteinases (MMP)1, MMP2, and COX-2 [9], co-opted from normal vascular remodeling, inflammation, and wound healing. Tellingly, several of these pivotal genes can be regulated by TGF-β. Although indisputably TGF-β plays both direct and indirect roles in tumor development and progression, which depending on context, may facilitate or impede cancer cells gaining a foothold [8], it is also a dominant force in dictating the host response to invading tumor cells [10], as discussed in this brief review.

Section snippets

TGF-β in head and neck squamous cell carcinoma (HNSCC)

One of the tumors associated with high mortality rates, because of its high infiltrative potential, is HNSCC which represents about 6% of all new cancers in the US [11] and for which the survival rate has not improved significantly in decades. Although a heterogeneous disease, a major and common etiological risk factor is continuous exposure of head and neck epithelia to environmental carcinogens, with genetic and epigenetic alterations in oncogenes or tumor suppressor genes. TGF-β is

TGF-β in immune dysregulation

Within the tumor site, TGF-β is sequestered in the extracellular matrix via latent TGF-β-binding protein (LTPB) and secreted from resident or recruited leukocytes, stroma and tumor cells [10] (Figure 1). In this dynamic microenvironment, TGF-β is a potent recruitment factor for inflammatory cells, which may not only participate in immune surveillance but also generate a sanctuary conducive to tumor escape. Despite local infiltration of the key players needed to orchestrate antitumor immunity (

TGF-β suppression of tumor immunity

The tumor appears undaunted by the complexity and intensity of the immune cell interactions coordinated as an impediment to its existence and in fact, seems to exploit these pathways to create a beneficial tolerogenic environment. In the evolving events, tumor-derived TGF-β and/or other mediators may effectively impair the function of immune cells involved both in tumor recognition and effector antitumor responses. For example, APC, notably DC [26], and macrophages are crucial elements in

Regulatory T cells and TGF-β

In addition to its direct immunoregulatory powers, TGF-β also coordinates its immunosuppressive functions through the conduit of Tregs. Different subtypes of Tregs, molded within the tumor milieu, contribute to a tolerogenic environment. Regulatory type 1 (Tr1) lymphocytes, influenced by Cox2 and detected primarily by the expression of IL-10 and TGF-β, are associated with the inhibition of DC maturation and immunosuppression in HNSCC [34]. Naturally occurring CD4+CD25+Foxp3+ Treg whose primary

Conclusions

Clearly, within the context of a tumor environment, the forces impacting the tumor and the infiltrating components of the immune system, whose initial attempts to attack the tumor may be subverted to assist the tumor, are extremely complex. No cell type or its product(s) can be held accountable, but TGF-β appears to pervade the milieu and profoundly influence the behavior of not only transformed cells but also stromal cells and immune cells. TGF-β may directly support tumor growth through its

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This research was supported partly by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research.

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