Cancer Cell & Microenvironment

Combination therapy for the treatment of cancer is becoming increasingly essential as we gain improved understanding of the complexity of cancer progression and the mechanisms by which cancer cells become resistant to single-agent therapy. Recent studies, both clinical and preclinical, have suggested that immunotherapy is a promising approach to the treatment of cancer; however, strategies to improve its clinical efficacy are still needed. A number of recent studies have indicated that antiangiogenic tyrosine kinase inhibitors (TKIs) target multiple components of the tumor microenvironment and are an ideal class of agents for synergizing with cancer immunotherapy...

Myeloid-derived suppressor cells (MDSCs) are one of the major cell components responsible for cancer immune evasion. Studying mechanisms associated with the regulation of MDSCs is becoming appreciated as another way to manipulate immune responses. MicroRNAs (miRNAs) have been recognized as substances which may interact with MDSCs, and eight miRNAs including miR-17-5p, miR-20a, miR-223, miR-21, miR-155, miR-494, miR-690 and miR-101 are of particular interest regarding MDSC accumulation and function. We have reviewed the data supporting this activity of these entities...

The lethality of ovarian cancer stems from its propensity to involve the peritoneal cavity. However, the mechanisms that enable ovarian cancer cells to readily adapt to the peritoneal environment are not well understood. Here, we describe our recent studies in which we identified the mechanisms by which the transcription factor encoded by the patterning gene HOXA9 promotes the aggressive behavior of ovarian cancer. Firstly, we identified that HOXA9 promotes ovarian tumor growth and angiogenesis by activating the gene encoding transforming growth factor-β2 (TGF-β2), which in turn stimulates peritoneal fibroblasts and mesenchymal stem cells to acquire features of cancer-associated fibroblasts...

Patients with chronic myeloid leukemia (CML) are commonly treated with a specific inhibitor of BCR-ABL tyrosine kinase, imatinib mesylate (IM). Unfortunately, CML patients develop IM-resistance, which has emerged as a significant clinical problem. Somatic mutations, especially T315I mutation, in BCR-ABL kinase domain represent the most common mechanism underlying drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to overcome TKI-resistance...

The cancer stem cell (CSC) theory is an emerging concept that proposes a hierarchical nature of carcinogenesis, where a small number of tumor cells are capable of driving tumor growth. Despite many unanswered questions surrounding the cancer stem cell model, the hypothesis has rejuvenated hopes for formulating a novel therapeutic strategy for targeting the roots of cancer. This model predicts that cancer stem cells have the capacity to resist conventional radio- and chemotherapy and initiate disease recurrence...

mRNA translation and protein synthesis is an important determinant for cell metabolism and cell homeostasis. Perturbations in cellular homeostasis often result in activation of negative feedback loops as compensatory mechanisms. Although, these mechanisms are important for mammalian cells to adjust to environmental changes, they also pose a major challenge for targeted cancer therapy as they provide escape mechanisms for cancer cells. The mammalian target of rapamycin (mTOR) is a crucial regulator of mRNA translation, protein synthesis and metabolism and represents an attractive target for anticancer therapy...

Soft tissue sarcoma is a malignancy that develops from human soft tissues such as muscle, nerve, fat, and blood vessels. The World Health Organization classification comprises about 50 different histologic types of soft tissue sarcoma. Soft tissue sarcoma is treated most often with surgery. Chemotherapy and radiotherapy have shown only minor effects on patient survival in this disease. The overall 5-year survival rate of soft tissue sarcoma is 50%; it has not changed for the past several decades. A new class of therapeutic targets for soft tissue sarcoma was identified recently...

In addition to cancer cells, primary tumors are composed of a multitude of stromal cell types. Among others, the stromal cell types involved in tumor growth and progression include endothelial cells, fibroblasts, pericytes, stem cells and various cell types of immune origin. While the role of oncogenes or tumor suppressor proteins expressed in cancer cells has been extensively studied, far less is known about potential involvement of proteins expressed in stromal cell types present within the tumor microenvironment...

Remarkable progress has been made highlighting the importance of cap-dependent mRNA translation in cancer progression. 4E-BP1 is a translation initiation repressor by sequestering the mRNA cap-binding protein eIF4E and consequently inhibiting the translation of certain key oncogenic mRNAs encoding proteins for cell proliferation, survival, angiogenesis and malignancy. In most tumors, however, the repressive function of 4E-BP1 is compromised by reduction of its expression or phosphorylation mediated by oncogenic signaling pathways...

The cells that initiate and propagate cancer are important therapeutic targets. However, the progression from cells of origin to tumor-propagating cells is poorly defined for most human cancers. Mouse models indicate that both basal and luminal cells can initiate prostate cancer, while studies with human prostate tissue have demonstrated a role for basal cells in transformation. Our recent study provides evidence that a common cell of origin can produce alternative variants of human epithelial cancer. Our findings also reveal that the cell of origin that initiates cancer is not continuously required to maintain and propagate the disease...