Advances in Tumor-Stroma Interactions: Emerging Role of Cytokine Network in Colorectal and Pancreatic Cancer

Abstract

Cytokines are a family of soluble factors (Growth Factors (GFs), chemokines, angiogenic factors, and interferons), which regulate a wide range of mechanisms in both physiological and pathological conditions, such as tumor cell growth and progression, angiogenesis, and metastasis. In recent years, the growing interest in developing new cancer targeted therapies has been accompanied by the effort to characterize Tumor Microenvironment (TME) and Tumor-Stroma Interactions (TSI). The connection between tumor and stroma is now well established and, in the last decade, evidence from genetic, pharmacological, and epidemiological data supported the importance of microenvironment in tumor progression. However, several of the mechanisms behind TSI and their implication in tumor progression remain still unclear and it is crucial to establish their potential in determining pharmacological response. Many studies have demonstrated that cytokines network can profoundly affect TME, thus displaying potential therapeutic efficacy in both preclinical and clinical models. The goal of this review is to give an overview of the most relevant cytokines involved in colorectal and pancreatic cancer progression and their implication in drug response.

BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer

“…It is nowadays accepted that soluble factor networks are involved in tumor-stroma interactions; cytokines and chemokines production (including IL-8) may be sustained not only by cancer cells but also by stromal elements (namely fibroblasts, endothelial, and immune cells), in a bidirectional crosstalk 2 . In a complex TME, stromal and/or infiltrating immune cells may substantially contribute to IL-8 expression; IL-8 regulation, in turn, can be modulated by targeted agents, such as selective BRAF inhibitors, differentially in a genetically normal stromal compartment, as compared to the tumor cell compartment, in which the net effect of pathway inhibition appears to be dictated by the specific genetic landscape of the tumor.…”

“…Cytokine networks contribute to the development and progression of cancer, particularly in Colorectal Cancer (CRC), in which inflammation represents a critical aspect of disease progression 1 . Within the Tumor MicroEnvironment (TME), both stromal and cancer cells release cytokines/chemokines and growth factors, thereby contributing to the cytokine networks, which modulate the inflammatory/immunologic milieu of cancer tissues 2 .…”

Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance

“…A distinct characteristic of PDAC is its desmoplasia, consisting of a significant amount of cancer-associated fibroblasts (CAFs) and a very dense fibrotic stroma [51] [ Figure 2]. The CAFs are pro-inflammatory due to activation of several signaling factors including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription (STAT)-1 and STAT-3, and transforming growth factor (TGF)-β/SMAD [51][52][53][54] . These signaling factors cooperate in active cross-talk with cancer cells through paracrine signaling factors including chemokines, insulin-like growth factor, and proteases [52][53][54][55][56] .…”

“…The CAFs are pro-inflammatory due to activation of several signaling factors including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription (STAT)-1 and STAT-3, and transforming growth factor (TGF)-β/SMAD [51][52][53][54] . These signaling factors cooperate in active cross-talk with cancer cells through paracrine signaling factors including chemokines, insulin-like growth factor, and proteases [52][53][54][55][56] . Furthermore, several pro-stemness paracrine factors are secreted by distinct CAFs [56][57][58][59][60][61][62] and support the self-renewal and the stemness properties of initial PCSCs in tumors or promote the conversion of cancer cells into PCSCs [63] .…”

Colorectal cancer stem cells properties and features: evidence of interleukin-8 involvement

“…As extensively reviewed by our and other groups, cytokine network represents a pivotal aspect in TME and TSI: amid the plethora of soluble factors involved in CRC progression and drug resistance, IL-8 is now recognized as one of the major promoters of tumor progression [10] . Several types of cells (i.e., macrophages, HGF: hepatocyte growth factor; CSC: cancer stem cells; MSC: mesenchymal stem cells; PGE2: prostaglandin E2; CRC: colorectal cancer; EMT: epithelial-mesenchymal transition; JAG: jagged; CAF: cancer-associated fibroblasts; IL: interleukin; CIC: cancer initiate cells; STAT: signal transducer and activator of transcription; DOT1L: disruptor of telomeric silencing 1-like MSC, endothelial, epithelial and cancer cells) release IL-8 in TME: due the presence of its receptors, even in cells other than those which released IL-8, this chemokine is involved in promoting many features of cancer development, such as EMT, angiogenesis, tumor growth, metastasis and immunosuppressive microenvironment [59] .…”