Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

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Cancer-related inflammation.

Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?

New functions for the matrix metalloproteinases in cancer progression

Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

Cancer Metastasis: Building a Framework

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

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Involvement of chemokine receptors in breast cancer metastasis.

Background
A topic of great concern in bioethics is the medical research conducted in poor countries sponsored by wealthy nations. Western drug companies increasingly view Latin America as a proper place for clinical research trials. The region combines a large population, modern medical facilities, and low per capita incomes. Participants from developing countries may have little or non alternative means of treatment other than that offered through clinical trials. Therefore, the provision of a valid informed consent is important.

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Consenting of the vulnerable: the informed consent procedure in advanced cancer patients in Mexico

Long-term immune dysfunction after radiotherapy to the head and neck area.

Objective To induce tumor regression with immunotherapy and to characterize the histology. Setting National Institute of Cancerology, Mexico City, Mexico. Patients Thirteen patients with advanced squamous cell carcinoma of the head and neck region. Intervention A 21-day cycle of preoperative immunotherapy, including a single intravenous infusion of low-dose cyclophosphamide (300 mg/M2), 10 daily perilymphatic injections of a natural cytokine mixture (approximately 150 units interleukin-2 equivalence by enzyme-linked immunosorbent assay), daily oral indomethacin, and daily oral zinc with multivitamins. Outcome measures Pretreatment biopsies were performed to confirm the diagnosis and to characterize the lesion by standard pathologic criteria, including the degree of tumor-associated lymphocytes. Clinical responses were assessed at surgery, and the specimen was analyzed with respect to changes in tumor morphology and lymphoid and inflammatory infiltration (T and B lymphocytes, plasma cells, macrophages, granulocytes, and giant cells). The presurgical and postsurgical characteristics were ascribed percentages based on a representative section. Results Prior to treatment, on average the biopsies demonstrated 77% solid tumor with 14% stroma and 9% sparse infiltration of lymphocytes. After treatment, one patient had a complete clinical response and showed only residual inflammatory cells and fibrosis. One patient had no clinical or histologic response. Of the remaining 11 patients, 4 had partial, 6 had minor, and 1 had no response. Tumors were reduced an average of 41% (16% solid and 25% fragmented) and lymphoid infiltration increased to 45% without change in residual stroma. Conclusions The pathologic changes viewed in the context of the clinical findings indicate that this immunotherapy protocol induces immune regression of the tumor, mediated predominantly by T and B lymphocytes, and thus elicits a tumor-specific immune reaction.

Emma Verastegui

Papers

Involvement of chemokine receptors in breast cancer metastasis.

Consenting of the vulnerable: the informed consent procedure in advanced cancer patients in Mexico

Long-term immune dysfunction after radiotherapy to the head and neck area.

Histologic findings in patients with head and neck squamous cell carcinoma receiving perilymphatic natural cytokine mixture (IRX-2) prior to surgery.

A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck