Dual Roles for Immunity in Gastrointestinal Cancers

Abstract

Histopathologic examination reveals that most human tumors are associated with diverse immune cell infiltrates, but the roles of host reactions in disease pathogenesis and prognosis remain to be fully clarified. Recent investigations in genetically engineered murine tumor models have uncovered dual functions for immune responses during cancer development and progression. Alterations in tumor cell gene expression profiles and coding sequences may trigger the activation of cytotoxic lymphocytes, which act to restrain tumor growth. In contrast, persistent inflammatory reactions, which may be driven by infection, environmental toxins, or impaired immune regulation, create a microenvironment that fosters tumor cell growth, survival, invasion, and dissemination. The dynamic interplay of these competing responses appears to be a critical event in cancer pathogenesis, with tumor promotion and immune evasion proving dominant in clinically evident disease. Nonetheless, longitudinal studies of patient cohorts have demonstrated that particular histopathologic and genetic signatures of cytotoxic lymphocyte reactions provide important prognostic information. Here, we discuss the dual roles of immunity in cancer development, focusing on gastrointestinal malignancies, given the depth of recent insights into the mechanisms underlying these tumors.

CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer

“…Immunity in cancer is two-sided, as inflammatory conditions can be tumor-promoting, as also shown in CRC, or the cancer activates an inflammatory response that restrains the tumor progression. 27 We have no indication of any inflammatory condition prior to CRC diagnosis leading to an elevated cancer risk within the early-onset sample group, although this cannot be excluded. If the increased immune content is associated to age, this supports the hypothesis of the existence of underlying genetic alteration causing an early onset of disease.…”

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

“…The ZONAB-dependent survival pathway thus provides a possible therapeutic opportunity to target ZONAB to induce cell death in cancer cells. This survival pathway seems up-regulated in different types of carcinomas because ZONAB has been reported to be upregulated in cancers form different tissues (14)(15)(16)(17)(18)(19)(20). Therapeutic targeting of ZONAB might also improve the effectiveness of existing therapies, because depletion enhanced cell death in response to Taxol (Fig.…”

“…ZONAB is activated in different types of cancers (14)(15)(16)(17)(18)(19)(20); hence, it would be important to know whether and how ZONAB promotes cell survival in response to cytotoxic stress and proinflammatory signals because targeting such survival pathways offers therapeutic benefits.…”

Functio Laesa: Cancer Inflammation and Therapeutic Resistance

“…1 Inflammation marked by the recruitment of leukocytes, particularly neutrophils, macrophages, and eosinophils, is a near-universal hallmark of cancer that is directed by malignant cells, which seek to establish a microenvironment conducive to survival, growth, and metastasis. This inflammatory reaction can also act as a barrier to the efficacy of cytotoxic and immunotherapeutic interventions.…”