Machine learning and bioinformatic analyses link the cell surface receptor transcript levels to the drug response of breast cancer cells and drug off-target effects.

Breast cancer responds variably to anticancer therapies, often leading to significant off-target effects. This study proposes that the variability in tumour responses and drug-induced adverse events is linked to the transcriptional profiles of cell surface receptors (CSRs) in breast tumours and normal tissues. We analysed multiple datasets to compare CSR expression in breast tumours with that in non-cancerous human tissues. Our findings correlate the drug responses of breast cancer cell lines with the expression levels of their targeted CSRs. Notably, we identified distinct differences in CSR expression between primary breast tumour subtypes and corresponding cell lines, which may influence drug response predictions. Additionally, we used clinical trial data to uncover associations between CSR gene expression in healthy tissues and the incidence of adverse drug reactions. This integrative approach facilitates the selection of optimal CSR targets for therapy, leveraging cell line dose-responses, CSR expression in normal tissues, and patient adverse event profiles.

Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness.

Investigating the human genome is vital for identifying risk factors and devising effective therapies to combat genetic disorders and cancer. Despite the extensive knowledge of the "light genome", the poorly understood "dark genome" remains understudied. In this study, we integrated data from 20,412 protein-coding genes in Pharos and 8,395 patient-derived tumours from The Cancer Genome Atlas (TCGA) to examine the genetic and pharmacological dependencies in human cancers and their treatment implications. We discovered that dark genes exhibited high mutation rates in certain cancers, similar to light genes. By combining the drug response profiles of cancer cells with cell fitness post-CRISPR-mediated gene knockout, we identified the crucial vulnerabilities associated with both dark and light genes. Our analysis also revealed that tumours harbouring dark gene mutations displayed worse overall and disease-free survival rates than those without such mutations. Furthermore, dark gene expression levels significantly influenced patient survival outcomes. Our findings demonstrated a similar distribution of genetic and pharmacological dependencies across the light and dark genomes, suggesting that targeting the dark genome holds promise for cancer treatment. This study underscores the need for ongoing research on the dark genome to better comprehend the underlying mechanisms of cancer and develop more effective therapies.

The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis.

The extracellular matrix (ECM) is a ubiquitous member of the body and is key to the maintenance of tissue and organ integrity. Initially thought to be a bystander in many cellular processes, the extracellular matrix has been shown to have diverse components that regulate and activate many cellular processes and ultimately influence cell phenotype. Importantly, the ECM's composition, architecture, and stiffness/elasticity influence cellular phenotypes. Under normal conditions and during development, the synthesized ECM constantly undergoes degradation and remodeling processes via the action of matrix proteases that maintain tissue homeostasis. In many pathological conditions including fibrosis and cancer, ECM synthesis, remodeling, and degradation is dysregulated, causing its integrity to be altered. Both physical and chemical cues from the ECM are sensed via receptors including integrins and play key roles in driving cellular proliferation and differentiation and in the progression of various diseases such as cancers. Advances in 'omics' technologies have seen an increase in studies focusing on bidirectional cell-matrix interactions, and here, we highlight the emerging knowledge on the role played by the ECM during normal development and in pathological conditions. This review summarizes current ECM-targeted therapies that can modify ECM tumors to overcome drug resistance and better cancer treatment.

The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans.

In Africa, the burden of hypertension has been rising at an alarming rate for the last two decades and is a major cause for cardiovascular disease (CVD) mortality and morbidity. Hypertension is characterised by elevated blood pressure (BP) ≥ 140/90 mmHg. Current hypertension guidelines recommend the use of antihypertensives belonging to the following classes: calcium channel blockers (CCB), angiotensin converting inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, ß-blockers, and mineralocorticoid receptor antagonists (MRAs), to manage hypertension. Still, a considerable number of hypertensives in Africa have their BP uncontrolled due to poor drug response and remain at the risk of CVD events. Genetic factors are a major contributing factor, accounting for 20% to 80% of individual variability in therapy and poor response. Poor response to antihypertensive drug therapy is characterised by elevated BPs and occurrence of adverse drug reactions (ADRs). As a result, there have been numerous studies which have examined the role of genetic variation and its influence on antihypertensive drug response. These studies are predominantly carried out in non-African populations, including Europeans and Asians, with few or no Africans participating. It is important to note that the greatest genetic diversity is observed in African populations as well as the highest prevalence of hypertension. As a result, this warrants a need to focus on how genetic variation affects response to therapeutic interventions used to manage hypertension in African populations. In this paper, we discuss the implications of genetic diversity in CYP11B2, GRK4, NEDD4L, NPPA, SCNN1B, UMOD, CYP411, WNK, CYP3A4/5, ACE, ADBR1/2, GNB3, NOS3, B2, BEST3, SLC25A31, LRRC15 genes, and chromosome 12q loci on hypertension susceptibility and response to antihypertensive therapy. We show that African populations are poorly explored genetically, and for the few characterised genes, they exhibit qualitative and quantitative differences in the profile of pharmacogene variants when compared to other ethnic groups. We conclude by proposing prioritization of pharmacogenetics research in Africa and possible adoption of pharmacogenetic-guided therapies for hypertension in African patients. Finally, we outline the implications, challenges, and opportunities these studies present for populations of non-European descent.

Advances in surface modifications of the silicone breast implant and impact on its biocompatibility and biointegration.

Silicone breast implants are commonly used for cosmetic and oncologic surgical indications owing to their inertness and being nontoxic. However, complications including capsular contracture and anaplastic large cell lymphoma have been associated with certain breast implant surfaces over time. Novel implant surfaces and modifications of existing ones can directly impact cell-surface interactions and enhance biocompatibility and integration. The extent of foreign body response induced by breast implants influence implant success and integration into the body. This review highlights recent advances in breast implant surface technologies including modifications of implant surface topography and chemistry and effects on protein adsorption, and cell adhesion. A comprehensive online literature search was performed for relevant articles using the following keywords silicone breast implants, foreign body response, cell adhesion, protein adsorption, and cell-surface interaction. Properties of silicone breast implants impacting cell-material interactions including surface roughness, wettability, and stiffness, are discussed. Recent studies highlighting both silicone implant surface activation strategies and modifications to enhance biocompatibility in order to prevent capsular contracture formation and development of anaplastic large cell lymphoma are presented. Overall, breast implant surface modifications are being extensively investigated in order to improve implant biocompatibility to cater for increased demand for both cosmetic and oncologic surgeries.

What to Do for Increasing Cancer Burden on the African Continent? Accelerating Public Health Diagnostics Innovation for Prevention and Early Intervention on Cancers.

No other place illustrates the increasing burden of cancer than in Africa and in particular, sub-Saharan Africa. Many of the individuals to be diagnosed with cancer will be in low-resource settings in the future due to, for example, an increase in populations and aging, and high co-morbidity with infections with viruses such as human immunodeficiency virus (HIV) and human papillomavirus (HPV), as well as the presence of infectious agents linked to cancer development. Due to lack of prevention and diagnostic innovation, patients present with advanced cancers, leading to poor survival and increased mortality. HIV infection-associated cancers such as B cell lymphomas, Kaposi's sarcoma, and HPV-associated cancers such as cervical cancer are particularly noteworthy in this context. Recent reports show that a host of other cancers are also associated with viral infection and these include lung, oral cavity, esophageal, and pharyngeal, hepatocellular carcinoma, and anal and vulvar cancers. This article examines the ways in which diagnostic innovation empowered by integrative biology and informed by public health priorities can improve cancer prevention or early intervention in Africa and beyond. In addition, I argue that because diagnostic biomarkers can often overlap with novel therapeutic targets, diagnostics research and development can have broader value for and impact on medical innovation.

Integrins Within the Tumor Microenvironment: Biological Functions, Importance for Molecular Targeting, and Cancer Therapeutics Innovation.

Many cellular functions important for solid tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell attachment receptors. With recent studies emphasizing the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that considerable attention is being paid to integrins. Several integrin antagonists are under clinical trials, with many demonstrating promising activity in patients with different cancers. A deeper knowledge of the functions of integrins within the TME is still required and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This expert review offers the latest synthesis in terms of the current knowledge of integrins functions within the TME and as potential molecular targets for cancer therapeutics innovation.

Thanatechnology and the Living Dead: New Concepts in Digital Transformation and Human-Computer Interaction.

In a digital society, shall we be the authors of our own experience, not only during our lifetime but also after we die? We ask this question because dying and bereavement have become even harder, and much less private, in the digital age. New big data-driven digital industries and technologies are on the rise, with promises of interactive 3D avatars and storage of digital memories of the deceased, so they can continue to exist online as the "living dead" in a digital afterlife. Famous rock and roll icons like Roy Orbison, Frank Zappa, Ronnie James Dio, and Amy Winehouse have famously been turned into holograms that can once again give "live" performances on the touring circuit, often pulling in large audiences. Death studies, dying, and grief have become virtual in the 21st century. We live in truly unprecedented times for human-computer interactions. Thanatology is the scientific study of death, dying, loss, and grief. In contrast to the biological study of biological aging (cellular senescence) and programmed cell death (apoptosis), thanatology employs multiple professional lenses, medical, psychological, physical, spiritual, ethical, descriptive, and normative. In 1997, Carla Sofka introduced the term thanatechnology as "technological mechanisms such as interactive videodiscs and computer programs that are used to access information or aid in learning about thanatology topics." Onward to 2021, the advent of social media, the Internet of Things, and sensors that digitize and archive nearly every human movement and experience are taking thanatechnology, and by extension, digital transformation, to new heights. For example, what happens to digital remains of persons once they cease to exist physically? This article offers a critical study and snapshot of this nascent field, and the "un-disciplinary" sociotechnical issues digital thanatechnologies raise in relation to big data. We also discuss how best to critically govern this new frontier in systems science and the digital society. We suggest that new policy narratives such as (1) the right to nonparticipation in relation to information and communication technologies and (2) the planetary public goods deserve further attention to democratize thanatechnology and big data. To the extent that systems science often depends on data from online platforms, for example, in times of pandemics and ecological crises, "critical thanatechnology studies," introduced in this article, is a timely and essential field of scholarship with broad importance for systems science and planetary health.

Recent Trends in Multipotent Human Mesenchymal Stem/Stromal Cells: Learning from History and Advancing Clinical Applications.

Early cell biology reports demonstrated the presence of cells with stem-like properties in bone marrow, with both hematopoietic and mesenchymal lineages. Over the years, various investigations have purified and characterized mesenchymal stromal/stem cells (MSCs) from different human tissues as cells with multilineage differentiation potential under the appropriate conditions. Due to their appealing characteristics and versatile potentials, MSCs are leveraged in many applications in medicine such as oncology, bioprinting, and as recent as therapeutics discovery and innovation for COVID-19. To date, studies indicate that MSCs have varied differentiation capabilities into different cell types, and demonstrate immunomodulating and anti-inflammatory properties. Different microenvironments or niche for MSCs and their resulting heterogeneity may influence attendant cellular behavior and differentiation capacity. The potential clinical applications of MSCs and exosomes derived from these cells have led to an avalanche of research reports on their properties and hundreds of clinical trials being undertaken. There is ample reason to think, as discussed in this expert review that the future looks bright and promising for MSC research, with many clinical trials under way to ascertain their clinical utility. This review provides a synthesis of the latest advances and trends in MSC research to allow for broad and critically informed use of MSCs. Early observations of the presence of these cells in the bone marrow and their remarkable differentiation capabilities and immunomodulation are also presented.

The Role of Viruses in Carcinogenesis and Molecular Targeting: From Infection to Being a Component of the Tumor Microenvironment.

About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.

Cancer Stem Cell Marker CD44 Plays Multiple Key Roles in Human Cancers: Immune Suppression/Evasion, Drug Resistance, Epithelial-Mesenchymal Transition, and Metastasis.

One of the most frequently utilized cancer stem cell markers in human cancers, including colorectal cancer and breast cancer, is CD44. A glycoprotein, CD44, traverses the cell membrane and binds to many ligands, including hyaluronan, resulting in activation of signaling cascades. There are conflicting data, however, on expression of CD44 in relationship to subtypes of cancers. Moreover, the associations of CD44 expression with drug resistance, immune infiltration, epithelial-mesenchymal transition (EMT), metastasis, and clinical prognosis in several cancer types are not clear and call for further studies. We report here an original study on CD44 expression in several human cancers and its relationship with tumorigenesis. We harnessed data from the publicly available databases, including The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Oncomine, Genomics of Drug Sensitivity in Cancer, and the Tumor Immune Estimation Resource. Our analysis reveals that CD44 expression varies across cancer types and is significantly associated with cancer patients' survival, in gastric and pancreatic cancers (p < 0.05). In addition, CD44 expression is closely linked with immune infiltration and immune suppressive features in pancreatic, colon adenocarcinoma, and stomach cancer. High CD44 expression was significantly correlated with the expression of drug resistance, EMT, and metastasis associated genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients compared to tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anticancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cell-substrate adhesion, migration, platelet activation, and cellular response to stress. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling, and the response to stimulus. In summary, these findings lend evidence for the multiple key roles played by CD44 in tumorigenesis and suggest that CD44 is considered further in future studies of cancer pathogenesis and the search for novel molecular targets and personalized medicine biomarkers in clinical oncology.

Coronavirus Disease 19 and Future Ecological Crises: Hopes from Epigenomics and Unraveling Genome Regulation in Humans and Infectious Agents.

With coronavirus disease 19 (COVID-19), we have witnessed a shift from public health to planetary health and a growing recognition of the importance of systems science in developing effective solutions against pandemics in the 21st century. COVID-19 and the history of frequent infectious outbreaks in the last two decades suggest that COVID-19 is likely a dry run for future ecological crises. Now is the right time to plan ahead and deploy the armamentarium of systems science scholarship for planetary health. The science of epigenomics, which investigates both genetic and nongenetic traits regarding heritable phenotypic alterations, and new approaches to understanding genome regulation in humans and pathogens offer veritable prospects to boost the global scientific capacities to innovate therapeutics and diagnostics against novel and existing infectious agents. Several reversible epigenetic alterations, such as chromatin remodeling and histone methylation, control and influence gene expression. COVID-19 lethality is linked, in part, to the cytokine storm, age, and status of the immune system in a given person. Additionally, due to reduced human mobility and daily activities, effects of the pandemic on the environment have been both positive and negative. For example, reduction in environmental pollution and lesser extraction from nature have potential positive corollaries on water and air quality. Negative effects include pollution as plastics and other materials were disposed in unconventional places and spaces in the course of the pandemic. I discuss the opportunities and challenges associated with the science of epigenomics, specifically with an eye to inform and prevent future ecological crises and pandemics that are looming on the horizon in the 21st century. In particular, this article underscores that epigenetics of both viruses and the host may influence virus infectivity and severity of attendant disease.

COVID-19 Pandemic and Africa: From the Situation in Zimbabwe to a Case for Precision Herbal Medicine.

This opinion commentary on the coronavirus disease 2019 (COVID-19) pandemic brings together observations from Zimbabwe specifically, and Africa broadly, drawing from the fields of pharmacogenomics, precision herbal medicine, and responsible innovation so as to respond to the pandemic in ways that are efficient, critically informed, principled, and responsive to needs in rural and urban communities across Africa. With new findings suggesting that COVID-19 is a systemic disease, impacting the respiratory system and beyond in some individuals, we need new molecular targets for therapeutics innovation more than ever. We argue that the current pandemic will likely strip the limited resources from other diseases such as malaria, human immunodeficiency virus (HIV) infection, and among others affecting the African continent. Hence, we need to address not only COVID-19 but also its broader health care and societal impacts in Africa. Extensive diagnostic testing to trace and isolate the COVID-19 cases as well as basic income and economic support for those who are unable to work will be needed. A critically informed and democratic governance that builds on transparency and trust for the elected leaders is crucial. Finally, the pandemic offers a silver lining for Africa: the prospects to integrate omics research with long-standing expertise in herbal medicine in Africa, thus accelerating the advances toward novel molecular therapeutic targets for COVID-19 and precision herbal medicine worldwide.

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine.

Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is evolving across the world and new treatments are urgently needed as with vaccines to prevent the illness and stem the contagion. The virus affects not only the lungs but also other tissues, thus lending support to the idea that COVID-19 is a systemic disease. The current vaccine and treatment development strategies ought to consider such systems medicine perspectives rather than a narrower focus on the lung infection only. COVID-19 is associated with elevated levels of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ). Elevated levels of cytokines and the cytokine storm have been linked to fatal disease. This suggests new therapeutic strategies through blocking the cytokine storm. IL-6 is one of the major cytokines associated with the cytokine storm. IL-6 is also known to display pleiotropic/diverse pathophysiological effects. We suggest the blockage of IL-6 signaling and its downstream mediators such as Janus kinases (JAKs), and signal transducer and activators of transcription (STATs) offer potential hope for the treatment of severe cases of COVID-19. Thus, repurposing of already approved IL-6-JAK-STAT signaling inhibitors as well as other anti-inflammatory drugs, including dexamethasone, is under development for severe COVID-19 cases. We conclude this expert review by highlighting the potential role of precision herbal medicines, for example, the Cannabis sativa, provided that omics technologies can be utilized to build a robust scientific evidence base on their clinical safety and efficacy. Precision herbal medicine buttressed by omics systems science would also help identify new molecular targets for drug discovery against COVID-19.

Cancer Stem Cell Markers in Relation to Patient Survival Outcomes: Lessons for Integrative Diagnostics and Next-Generation Anticancer Drug Development.

Solid tumors display a complex biology that requires a multipronged treatment strategy. Most anticancer interventions, including chemotherapy, are currently unable to prevent treatment resistance and relapse. In general, therapeutics target cancer cells and overlook the tumor microenvironment (TME) and the presence of cancer stem cells (CSCs) with self-renewal and tumorigenic abilities. CSCs have been postulated to play key roles in tumor initiation, progression, therapy resistance, and metastasis. Hence, CSC markers have been suggested as diagnostics to forecast cancer prognosis as well as molecular targets for new-generation cancer treatments, especially in resistant disease. We report here original findings on expression and prognostic significance of CSC markers in several cancers. We examined and compared the transcriptional expression of CSC markers (ABCB1, ABCG2, ALDH1A1, CD24, CD44, CD90, CD133, CXCR4, EPCAM, ICAM1, and NES) in tumor tissues versus the adjacent normal tissues using publicly available databases, The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis. We found that CSC transcriptional markers were, to a large extent, expressed in higher abundance in solid tumors such as colon, lung, pancreatic, and esophageal cancers. On the other hand, no CSC marker in our analysis was expressed in the same pattern in all cancers, while individual CSC marker expression, alone, was not significantly associated with overall patient survival. Innovation in next-generation cancer therapeutics and diagnostics ought to combine CSC markers as well as integrative diagnostics that pool knowledge from CSCs and other TME components and cancer cells.

Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review.

Despite great strides being achieved in improving cancer patients' outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance.

The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.

Broadening Drug Design and Targets to Tumor Microenvironment? Cancer-Associated Fibroblast Marker Expression in Cancers and Relevance for Survival Outcomes.

Solid tumors have complex biology and structure comprising cancer cells, stromal cells, and the extracellular matrix. While most therapeutics target the cancer cells, recent data suggest that cancer cell behavior and response to treatment are markedly influenced by the tumor microenvironment (TME). In particular, the cancer-associated fibroblasts (CAFs) are the most abundant stromal cells, and play a significant contextual role in shaping tumor initiation, progression, and metastasis. CAFs have therefore emerged as part of the next-generation cancer drug design and discovery innovation strategy. We report here new findings on differential expression and prognostic significance of CAF markers in several cancers. We utilized two publicly available resources: The Cancer Genomic Atlas and Gene Expression Profiling Interactive Analysis. We examined the expression of CAF markers, ACTA2, S100A4, platelet-derived growth factor receptor-beta [PDGFR-ß], CD10, and fibroblast activation protein-alpha (FAP-α), in tumor tissues versus the adjacent normal tissues. We found that CAF markers were differentially expressed in various different tumors such as colon, breast, and esophageal cancers and melanoma. No CAF marker is expressed in the same pattern in all cancers, however. Importantly, we report that patients with colon adenocarcinoma and esophageal carcinoma expressing high FAP-α and CD10, respectively, had significantly shorter overall survival, compared with those with low levels of these CAF markers (p < 0.05). We call for continued research on TME biology and clinical evaluation of the CAF markers ACTA2, S100A4, PDGFR-ß, CD10, and FAP-α in relation to prognosis of solid cancers in large population samples. An effective cancer drug design and discovery roadmap in the 21st century ought to be broadly framed, and include molecular targets informed by both cancer cell and TME variations.