Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte‐macrophage colony‐stimulating factor and contained CD34 natural suppressor cells

Abstract

Human head and neck squamous cell carcinomas (HNSCC) that produce high levels of granulocyte-macrophage colonystimulating factor (GM-CSF) have been shown to contain CD34 1 natural suppressor cells that inhibit the activity of intratumoral T-cells. The present study evaluated whether GM-CSF production and the presence of CD34 1 cells within primary HNSCC would translate into increased recurrence, metastasis or cancer-related death during the 2 years following surgical excision. Freshly excised primary HNSCC of 20 patients that subsequently developed disease, and of 17 patients that remained with no evidence of disease were analyzed for production of GM-CSF and for CD34 1 cell content. The cancers of patients that subsequently developed recurrences or metastatic disease produced almost 4-fold the levels of GM-CSF and had approximately 2.5-fold the number of CD34 1 cells as did cancers of patients that remained disease-free. In a second method of analysis, the prognostic significance of high vs. low GM-CSF and CD34 1 cell values was evaluated. These analyses showed that patients whose cancers produced high GM-CSF levels or had a high CD34 1 cell content had a disproportionately high incidence of recurrence or metastatic disease (94% and 100%, respectively), while the majority of patients whose primary cancers produced low levels of GM-CSF or had a low CD34 1 cell content remained disease-free (16% and 19%, respectively). Our results indicate that the presence of CD34 1 cells in GM-CSFproducing HNSCC is associated with a poorer prognosis for the cancer patients and suggest the utility of these parameters as prognostic indicators of outcome. Mechanistically, our results suggest that the presence of immune suppressive CD34 1 cells in GM-CSF-producing HNSCC leads to increased tumor recurrence or metastasis. Int. J. Cancer 74:69-74.r 1997 Wiley-Liss, Inc.Head and neck cancers, most of which are squamous cell carcinomas (HNSCC), are vulnerable to immune effector cells such as macrophages, natural killer cells and cytotoxic T-lymphocytes (Chikamatsu et al., 1995;Rabinowich et al., 1992). However, patients with HNSCC cancers are particularly prone to have defects in their immune defenses (Gooding et al., 1995;Hadden et al., 1994). Part of this immune suppression has been shown to be directly induced by soluble immune suppressive factors produced by the cancer (O'Mahony et al., 1993). However, cancers can also mediate immune suppression indirectly by stimulating immune suppressor cell activity. The immune suppressor cells that may be induced by human HNSCC have not been extensively studied or described, but have been well documented in many other cancer types of both humans and animals. Some human cancers induce suppressive T-cells that are inhibitory to immune functions, including anti-tumor T-cell reactivities (Chakraborty et al., 1991). Suppression of T-cell function in patients with HNSCC as well as with other cancers can also be due to monocytes or macrophages secreting the immune suppressive mediator prostaglandin E 2...

Growth Regulated Oncogene-α expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC Receptor-2 dependent mechanism

“…The increase in mGRO-a expression was associated with an increase in vascular density and in®ltration of polymorphonuclear and mononuclear leukocytes in PAM-KC tumors. Increased vascular density and in®ltration of polymorphonuclear and mononuclear leukocytes has previously been associated with increased growth, metastasis and a decrease in prognosis in human and murine tumors (Pak et al, 1995;Gasparini et al, 1993;Young et al, 1997;Gutman et al, 1994;Seung et al, 1995). These results provide evidence that the increased expression of CXC chemokines such as mGRO-a by SCC can induce host responses which provide a selective advantage for malignant growth in vivo.…”

“…While the potential advantage of increased vascular supply has been well accepted (Weidner and Folkman, 1996), the mechanisms by which in¯ammatory responses may promote malignant behavior have not been fully de®ned. Seung, Pekarek and colleagues have shown that granulocytes can promote growth of UV induced skin tumors (Seung et al, 1995;Pekarek et al, 1995), and Young and colleagues have shown that CD34+ cells of the granulocyte lineage induced by SCC can promote both growth, metastasis and immune suppression (Pak et al, 1995;Young et al, 1997). GRO-a and IL-8 are chemoattractants which are e ective in recruiting granulocytes and macrophages.…”

“…In¯ammatory and angiogenesis responses are commonly observed in SCC (Pak et al, 1995;Gasparini et al, 1993;Young et al, 1997), and human GRO-a has been shown to promote an increase in neutrophil chemotaxis and vessel density (Strieter et al, 1996). We examined PAM 212 tumors and PAM metastases for evidence of in¯ammatory and vascular changes, since we showed in Figure 1b that PAM 212 expresses low levels of KC while PAM metastases express KC at increased levels.…”

“…Development of SCC and other cancers is often associated with increased leukocyte in®ltration and angiogenesis (Pak et al, 1995;Gasparini et al, 1993), and increased density of leukocytes and blood vessels has been associated with a higher risk of progressive tumor growth, metastasis, and death in patients (Gasparini et al, 1993;Young et al, 1997) and in experimental animal models (Gutman et al, 1994;Seung et al, 1995). Identi®cation of the factor(s) that induce these in¯ammatory and angiogenesis responses, and their role in promotion of malignant progression, has been the subject of considerable interest to investigators studying SCC and other cancers (Schreiber and Rowley, 1999).…”

Densidade microvascular no carcinoma de língua

“…Estas células causam imunossupressão local, podem estimular a angiogênese e têm sido associadas com pior prognóstico [10][11][12] . Embora estas células tenham sido identificadas no presente estudo, o CD34 é um marcador de membrana e o método imuno-histoquímico empregado não é adequado para a sua quantificação.…”