Nigel P. Murray

Prostate cancer is formed of a heterogeneous population of cancer cells with different biological properties. They initially form a small part of the normal stromal microenvironment but are able, through cell-to-cell contact and via exosomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, and chemokines and cytokines, to transform the normal stromal cells into tumour-associated cells to create an immunosuppressive environment as well as inhibit the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement membrane but also the extracellular matrix, allowing the exosomes to disseminate via the circulation. Exosomes are organotrophic, homing in to specific tissues such as bone. Here, they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environment, as well as induce changes in the host cells and produce myeloid-derived suppressor cells, of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response, they are able to implant in the premetastatic niche, transforming it into the metastatic niche. Here, they enter a latent state or dormancy period, which may last for months or years but later can “awake” to form metastasis. This review critically analyses the cellular and molecular mechanisms, which produce this process from cellular aspects to the signalling pathways responsible for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells, from cellular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNAs and long non-coding RNAs in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survival at 10 years. Therefore, a precision medical approach may improve the biochemical free survival rate without affecting the role of the signalling pathways in normal cells. This includes the modulation of interleukin expression, elimination of exosomes, or the inhibition of important enzymes, such as MMP-2, thus mitigating the residual recurrence risk that persists with conventional therapy.

Prostate cancer is formed of a hetergeneous population with different biological properties.They initially form a small part of the normal stromal microenviroment, but are able through cell to cell contact and via exsomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, chemokines and cytokines are transform the normal stromal cells into tumour associated cells to create an immunosuppressive environment as well as inhibiting the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement mnbrane but also the extracelular matrix allowing the exosomes to disseminate via the circulation. They are organotrophic, homing in to specific tissues such as bone. Here they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environement as well as inducing changes in the host cells, producing myeloid derived suppressor cells of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response they are able to implant in the premetastatic niche transforming it into the metastatic niche. Here they enter a latent state or dormancy which may last for months or years, but later can “awake” to form metastasis. This review critically analyzes the celular and molecular mechanisms which produce this process from celular aspects to the signaling pathways responsable for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells; from celular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNA and long non-coding RNA in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survial at ten years. Therefore, a precisión medical approach may improve the biochemical free survival rate without affecting the role of these signaling pathways in normal cells. This includes the modulation of interleukin expresion,elimination of exosomes or the inhibition of important enzymes such as MMP-2 thus mitigating the residual recurrence risk that persists with conventional therapy.

Breast cancer is the most common cancer in women, depending on the sub-type of breast cancer treatment options are different. After completing adjuvant therapy, there are patients who may relapse even many years later. This review examines minimal residual disease, defined as small, microscopic foci of cancer cells that have survived curative treatment, have disseminated to distant tissues, and implanted there. However, the cancer cells do not exist alone but are a small part of the tumour microenvironment, described as an ecosystem. This includes stromal cells, immunosuppressive regulatory T-cells, myeloid derived suppression cells, cancer associated fibroblasts, tumour associated macrophages. The balance of the immunosuppressive tumour microenvironment and the anti-tumour immune response will determine if there is a future relapse. The interactions between the cancer cells and the tumour microenvironment are dynamic and change with time. Most therapeutic options involve therapies directed against tumour cells, only in the last few years has there been attention on the dynamic effects of the tumour microenvironment and the cancer cells on disease progression and the possibility of decreasing the risk of metastatic disease. This article reviews the latest development in preventing metastatic disease by influencing the tumour microenvironment; at best eliminating cancer cells or at least prolonging the latent period of cancer cell dormancy.

Breast cancer is the most common cancer in women, depending on the sub-type of breast cancer treatment options are different. After completing advujant therapy, there may relapse even many years later. This review examines the tumour microenvironment, cancer cells do not exist alone but are a small part of the tumour microenvironment, described as an ecosystem. This includes stromal cells, immunosuppressive regulatory T-cells, myeloid derived suppression cells, cancer associated fibroblasts, tumour associated macrophages. The balance of the immunosuppressive tumour microenvironment and the anti-tumour immune response will determine if there is a future relapse. Most therapeutic options involve therapies directed against tumour cells, only in the last few years has there been attention on the effects of the tumour microenvironment on disease progression and the possibility of decreasing the risk of metastatic disease. This article reviews the latest development in preventing metastatic disease by influencing the tumour microenevironment; at best eliminating cancer cells or at least prolonging the latent period of cancer cell dormancy.

Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapies. It also considers when would be the optimal time to employ this type of therapy.

Rosacea is a common chronic inflammatory condition primarily affecting middle-aged women. It presents with flushing, erythema, telangiectasia, papules, pustules, phymatous changes, and ocular involvement. Although typically grouped into four subtypes—erythematotelangiectatic, papulopustular, ocular, and phymatous—overlapping features often favor a phenotypic diagnostic approach. Neurogenic rosacea (NR) has emerged as a distinct subgroup featuring distinguishing features such as peripheral facial erythema, severe burning and stinging sensations, and resistance to standard rosacea therapies. Recent insights into the pathophysiology of NR propose neural dysregulation as the main driver of the condition. Specifically, the activation of TRP channels at cutaneous sensory nerve endings in the dermis triggers the release of vasoactive peptides, driving neuroinflammation and resulting in burning and stinging. Additionally, there is a marked association with neuropsychiatric comorbidities, which would further mediate the pathogenesis of the condition. In line with this pathophysiological model, NR often fails to respond to conventional rosacea treatments. Instead, patients benefit more from antidepressants and neuroleptic agents that help modulate neuronal activity and alleviate symptoms. This review explores and summarizes the scientific evidence regarding the new insights on disease pathogenesis, clinical manifestations, and proposed treatments for NR.

Immunotherapy alone or incombination with chemotherapy or radioitherapy is in the front line treatment for melanoma and lung cancer.However, its role in prostate cancer is usually as fourth line treatment. It is usual employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapy. It als considers when would be the optimal time to employ this type of therapy.

Intravascular large B‐cell lymphoma (IVLCBL) is a rare form of non‐Hodgkin’s lymphoma and is characterized by the growth of large B‐cells within blood vessels and bone marrow sinusoids. A 55‐year‐old man presented with a multiple endocrine failure which progressed to a pancytopenia. A bone marrow biopsy revealed a diffuse infiltration by large B‐cells in the sinusoids consistent with intravascular lymphoma. After 6 cycles of R‐CHOP, complete remission was achieved. Six months later, the patient relapsed presenting with a thrombotic microangiopathy which progressed to multiple organ failure and death.

Matrix metalloproteinase-2 (MMP-2) is a gelatinase and is involved in multiple steps of the metastatic cascade. More than a decade ago an increased expression of MMP-2 in tumour cells or higher serum levels was reported to be a prognostic biomarker for a lower disease-free and overall survival rate. In recent years new evidence has indicated that MMP-2 has an important role in the tumour ecosystem. It is one of the many players in the onco-sphere, involved in interacting between tumour cells, host cells and the microenvironment. It plays a role in the dissemination of tumour cells, the epithelial–mesenchymal and mesenchymal–epithelial transitions, the formation of the pre-metastatic and metastatic niches, dormancy of tumour cells and modulating the immune system. The aim of this review is to highlight these multiple roles in the metastatic cascade and how many signalling pathways can up or down-regulate MMP-2 activity in the different stages of cancer progression and the effect of MMP-2 on the onco-sphere. Research in head and neck cancer is used as an example of these processes. The use of non-specific MMP inhibitors has been unsuccessful showing only limited benefits and associated with high toxicity as such that none have progressed past Phase III trials. Preclinical trials are undergoing using antibodies directed against specific matrix metalloproteinases, these targeted therapies may be potentially less toxic to the patients.

Aims: To determine the association of micro-metastatic matrix metalloproteinase-2 (MMP-2) expression, the absolute lymphocyte count (ALC)) and outcome in stage II colon cancer. Materials and Methods: A single centre, prospective observational study, one month post-surgery blood for ALC, circulating tumour cell (CTC) detection and a bone marrow biopsy for micro-metastasis detection were obtained. CTCs were detected using differential gel centrifugation and immunocytochemistry with anti-CEA and anti-MMP-2, the bone marrow biopsy for the detection of micro-metastasis was processed as for CTCs . At each follow-up ALC and CTC counts were determined. Bone marrow sampling was repeated if the ALC decreased by >10%, at relapse or at the end of the study period. Three MRD subgroups were defined, Group I MRD negative, Group II only positive for micro-metastasis and Group III in which CTCs were detected. Results: One hundred and eighty one patients participated; 105 (58%) patients formed Group 1, 36 (20%) formed Group II and 40 (22%) formed Group III for a median follow-up of 4 years . Of Group I 3/105 (3%), Group II 16/36 (44%) and Group III 34/40 (84%) patients relapsed. The ALC was significantly higher in Groups I and II, the expression of MMP-2 and MMP-2 score in Group II was significantly lower than in Group III patients. A low ALC was associated with a higher expression of MMP-2 in the micro-metastasis and presence of CTCs. Conclusions: Patients with stable ALCs did not relapse; decreasing ALCs were associated with increasing MMP-2 scores, the appearance of CTCs and relapse.