https://escholarship.org/content/qt5st231s3/qt5st231s3.pdf?t=omsseb

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

The Cancer Stem Cell Niche: How Essential Is the Niche in Regulating Stemness of Tumor Cells?

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

/pdf/molecular-principles-of-metastasis-a-hallmark-of-cancer-2owibp00tb.pdf

Molecular principles of metastasis: a hallmark of cancer revisited

Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.

/pdf/concepts-of-extracellular-matrix-remodelling-in-tumour-2m26t5qipg.pdf

Concepts of extracellular matrix remodelling in tumour progression and metastasis

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

/pdf/the-biology-and-role-of-cd44-in-cancer-progression-2ly9zcn4zw.pdf

The biology and role of CD44 in cancer progression: Therapeutic implications

During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

https://www.mdpi.com/2072-6694/6/3/1670/pdf

Tumor-associated macrophages as major players in the tumor microenvironment.

Hyaluronan: A modulator of the tumor microenvironment.

Cancer stem cells (CSCs) represent a unique subpopulation of self-renewing oncogenic cells that drive cancer initiation and progression. CSCs often acquire multidrug and oxidative stress resistance and are thereby thought to be responsible for tumor recurrence following treatment and remission. Although the mechanisms responsible for CSC generation, maintenance, and expansion have become a major focus in cancer research, the molecular characteristics of CSCs remain poorly understood. The stemness and subsequent expansion of CSCs are believed to be highly influenced by changes in microenvironmental signals as well as genetic and epigenetic alterations. Hyaluronan (HA), a major component of the extracellular matrix, has recently been demonstrated to provide a favorable microenvironment for the self-renewal and maintenance of stem cells. HA directly and indirectly affects CSC self-renewal by influencing the behavior of both cancer and stromal cells. For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition. The importance of HA in mediating CSC self-renewal has been strengthened by the finding that interactions between HA and its receptor, CD44, propagate the stemness of CSCs. HA-CD44 interactions evoke a wide range of signals required for CSC self-renewal and maintenance. CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals. Thus, a better understanding of the molecular mechanisms involved in HA and CD44 control of CSC stemness may help in the design of more effective therapies for cancer patients. In this review, we address the key roles of HA and CD44 in CSC self-renewal and maintenance. We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

/pdf/key-roles-of-hyaluronan-and-its-cd44-receptor-in-the-31mor3dcd9.pdf

Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Background and Aims:  The role of glypican-3 (GPC3), a novel serum marker, in differentiating hepatocellular carcinoma (HCC) from non-malignant chronic liver disease and other malignant space-occupying lesions in the liver is largely unknown The aims of this study were to evaluate its diagnostic role and clinical correlations in patients with HCC



Methods:  Six groups were studied which included 40 healthy subjects, 50 patients with chronic hepatitis (CH), 50 patients with liver cirrhosis (LC), 100 patients with HCC, 50 patients with intrahepatic cholangiocarcinoma (ICC) and 50 patients with metastatic carcinoma (MCA) Serum GPC3 levels were measured by using a sandwich enzyme-linked immunosorbent assay method



Results:  Fifty-three percent of HCC patients had elevated serum GPC3 levels with values ranging 355–78266 ng/mL The serum marker was undetectable in other groups except one patient (2%) with LC and another patient (2%) with MCA In most cases of HCC, elevated GPC3 values did not correlate with α-fetoprotein (AFP) levels Detectable GPC3 was significantly correlated with the presence of viral hepatitis markers but was not correlated with tumor size and stage of HCC Serum GPC3 was superior to AFP in detecting small HCC (563% and 313%, respectively) A combination of serum GPC3 and AFP yielded an improved sensitivity for detecting small HCC to 75%



Conclusion:  Serum GPC3 is highly specific for detecting HCC The combined use of serum GPC3 and AFP provides a potentially promising tool to better differentiate HCC from benign liver disorders, as well as from other liver cancers

Diagnostic role of serum glypican‐3 in differentiating hepatocellular carcinoma from non‐malignant chronic liver disease and other liver cancers

Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis *♦

Theerawut Chanmee

Papers

Tumor-associated macrophages as major players in the tumor microenvironment.

Hyaluronan: A modulator of the tumor microenvironment.

Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Diagnostic role of serum glypican‐3 in differentiating hepatocellular carcinoma from non‐malignant chronic liver disease and other liver cancers

Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis *♦