Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation.

The primary physiological process of respiration produces carbon dioxide (CO2) that reacts with water molecules which subsequently liberates bicarbonate (HCO-3) and protons. Carbonic anhydrases (CAs) are the primary catalyst involved in this conversion. More than 16 isoforms of human CAs show organ or subcellular specific activity. Dysregulation of each CA is associated with multiple pathologies. Out of these members, the overexpression of membrane-bound carbonic anhydrase IX (CAIX) is associated explicitly with hypoxic tumors or various solid cancers. CAIX helps tumors deal with higher CO2 by sequestering it with bicarbonate ions and helping cancer cells to grow in a comparatively hypoxic or acidic environment, thus acting as a pH adaptation switch. CAIX-mediated adaptations in cancer cells include angiogenesis, metabolic alterations, tumor heterogeneity, drug resistance, and regulation of cancer-specific chemokines. This review comprehensively collects and describe the cancer-specific expression mechanism and role of CAIX in cancer growth, progression, heterogeneity, and its structural insight to develop future combinatorial targeted cancer therapies.

Integration of chemokine signaling with non-coding RNAs in tumor microenvironment and heterogeneity in different cancers.

Chemokines are small secreted proteins that regulate the immune system by signaling through chemokine receptors to induce immune cell migration, motility, and infiltration into the tissue. Altered chemokine/receptor expression is associated with numerous inflammatory diseases, and more recently in non-immune cell diseases like cancer. Emerging new studies demonstrate that chemokines can directly modulate the tumor microenvironment (TME) to assist tumorigenesis by regulating proinflammatory signaling, immune cell infiltration,and metastasis. However, the diversity and complexity in the regulation of chemokine expression and how chemokine receptor signaling influences TME needs comprehensive understanding. One mechanistic pathway that has shown promising early results in targeting tumor progression is the non-coding RNAs (ncRNAs). These are widely expressed and designated as prime gene regulatory factors in tumors and the immune system. Notably, ncRNAs have been implicated in regulating chromatin stability, translation of cytoplasmic mRNAs, and the functional regulation of membrane-less nuclear bodies, which are significant pathways implicated in tumorigenesis. Tissue-specific patterns of expression of ncRNAs have suggested their role as potential cancer biomarkers, providing a suitable rationale for targeting them clinically. In this review, we discuss the recent findings which demonstrate the role of differential expression of chemokines and ncRNA in modulating TME during tumor progression. We also discuss the communication between tumor and immune effector cells via chemokine/ncRNAs and identify their potential as novel therapeutic targets.